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LIPIDS

Lipids (General Properties, Classification of lipids, Importance), Fatty acids (General properties, Types), Essential fatty acids (Properties, Dietary source, Functions of Omega 3 & Omega 6 fatty acids, Ratio of Omega 3 & Omega 6 fatty acids), Level of different types of lipid in the human body, Cholesterol (Structure, Metabolic pathway, Related disease), Membrane lipid (Types, Function), Phospholipids (Location, Function, Types, Amphipathic nature), Ecosanoids, Enterohepatic circulation of Bile acids and Bile salts, The rate limiting step in bile acid synthesis, Prostaglandins, NSAIDs, COX-1 and COX-2, Diets rich in Marine lipids, Synthetic Lipid, The occurrence of main lipids in the human body, HDL is more important than VLDL

Advanced Nutrition Course No. FN – 501 Chapter No. 3 Lipids Assignment submitted to Rehana Begum Assistant Professor Department of Food and Nutrition Science College of Home Economics, Azimpur, Dhaka. 1 Maesha Musarrat (Lipids) Submitted by Serial No. Name of the Student Class roll 1 Maesha Musarrat 2336 2 Sharmin Akter Mina 2337 3 Sadia Rahman Kana 2338 4 Sadia Nusrat Bushra 2339 5 Farhana Yeasmin 2340 2 Maesha Musarrat (Lipids) Contents ❖ Lipids  General Properties  Classification of lipids  Lipids are of great importance to the body ❖ Fatty acids  General properties  Types of fatty acids ❖ Essential fatty acids  Omega-3 Fatty acid (2014, 2012, 2011)  Sources of Omega 3 Fatty acids  Functions of omega 3 fatty acids  Omega-6 fatty acid (2014, 2012, 2011)  Dietary sources of omega-6 fatty acids include  Functions of omega 6 fatty acids  Omega-6/Omega-3 ratio (2011, 2009, 2008) ❖ Level of different types of lipid in the human body ❖ Cholesterol  Structure of Cholesterol:  The Pathways of Cholesterol Metabolism (2014, 2011, 2008) ▪ Endogenous pathway ▪ Exogenous pathway ▪ Reverse cholesterol pathway  Diseases related to Cholesterol metabolism (2014, 2011) ▪ Hypercholesterolemia ▪ Hypocholesterolemia 3 Maesha Musarrat (Lipids) ❖ Membrane lipid(2008, 2010)  Types of membrane lipids  Functions of membrane lipids ❖ Phospholipids(2012)  Location  Amphipathic nature of phospholipids (2010)  Classification of Phospholipids (2010)  Functions of Phospholipids ❖ Ecosanoids (2014, 2013, 2009)  E osa oids are Lo al Hor o es  Major pathways of eicosanoids metabolism (2012) ▪ (Role of Cyclooxygenase) 2008 ▪ (Role of Lipooxygenase) 2008 ❖ Enterohepatic circulation of Bile acids and Bile salts (2010) ❖ The rate limiting step in bile acid synthesis (2012) ❖ Prostaglandins  Structure of Prostaglandins  Synthesis of Prostaglandins  Biochemical Functions of Prostaglandins (2010) ❖ NSAIDs (2010)  Classification of NSAIDs  Most Common Types of NSAIDs  Other Forms of NSAIDs  Medical uses of NSAIDs  Mechanism of action of NSAIDs  Antipyretic activity of NSAIDs  Risks associated with using NSAIDs 4 Maesha Musarrat (Lipids) ❖ COX-1 and COX-2 (2014, 2009) ❖ Diets rich in Marine lipids (2012)  Decrease cholesterol level  Decrease prostaglandin level  Decrease leukotrine level ❖ Synthetic Lipid (2013, 2012, 2010)  Examples of synthetic lipid  Synthetic Phospholipid derivatives  Functions of synthetic lipids ❖ The occurrence of main lipids in the human body (2014) ❖ HDL is more important than VLDL (2009) 5 Maesha Musarrat (Lipids) ❖ Lipids In biology, lipids comprise a group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E, and K), monoglycerides, diglycerides, triglycerides, phospholipids, and others. The term lipid was 1st used by the German biochemist Bloor in 1943 for a major class of tissue components and foodstuffs. Origin  General Properties • • • • • • Heterogenous group of compounds, greasy/oily organic substances, insoluble in water, soluble in organic solvents (alcohol, benzene, chloroform, ether etc), hydrophobic in nature, Unlike the polysaccharides, proteins and nucleic acids, lipids are not polymers. Further, lipids are mostly small molecules. 6 Maesha Musarrat (Lipids)  Classification of lipids Simple Lipids: Esters of fatty acids with alcohols Complex lipids: Esters of fatty acids with alcohols containing additional groups such as phosphate, nitrogen base, CHO, protein etc. (a) Fats and oils (triacylglycerols): • esters of glycerol and fatty acids: e.g. triacylglycerols • Differece between fat and oil is physical. Oil is liquid while fat is solid at room temperature. (b)Waxes: • esters of long-chain fatty acids and alcohols other than glycerols • Ceityl alcohol is most commonly used (a) Phosphplipids: contain phosphoric acid and frequently a nitrogenous base. This is in addition to alcohol and fatty acids. I. Glycerophopholipids: contain glycerol as the alcohol e.g. lecithin, cephalin II. Sphingophosphplipids: contain sphingosine as the alcohol e.g. sphingomyelin (b) Glycolipids / Glycosphingolipids: • Contain a fatty acid, carbohydrate, sphingosine and nitrogenous base. • Glycerol and phosphate are absent e.g. cerebroside, gangliosides. (c) Lipoproteins: • Macromoleculer complexes of lipids with proteins. • e.g. LDL, VLDL, chylomicrons, HDL etc. (d) Other complex lipids: Sulpholipids, aminolipids and lipopolysaccharides come under this 7 Maesha Musarrat (Lipids) Derived lipids Miscelleaneous lipids Neutral lipids • These are the derivatives of hydrolysis of simple and complex lipids which possess the characteristics of lipids. • These include: -Lipid soluble vitamins -Steroid hormones -Hydrocarbons -Ketone bodies -Mono and diacylglycerol ,etc • A large number of compounds possess characteristics of lipids,such compounds come under this category • Example:carotenoids,squalene,hydrocarbons like pentacosone and terpenes etc. • These are the lipids which are uncharged and are reffered ro as neutral lipids. • These are mono, di and triacylglycerols, cholesterol and cholesterol esters.  Lipids are of great importance to the body  Together with carbohydrates and proteins lipids constitute the principal structural materials of living cells  Concentrated storage form of energy  Serve as an insulating material in the subcutaneous tissues and around certain organs and give shape and smooth appearance to the body.  Serve as efficient source of energy (triacylglycerols) which is stored in the adipose tissue  Lipids combined with proteins (lipoproteins) are important constituents of the cell membranes (which regulate the membrane permeability) and mitochondria of the cell.  Lipids are important as cellular metabolic regulators (steroid hormones and prostaglandins).  They serve as a source of fat soluble vitamins (A, D, E & K) 8 Maesha Musarrat (Lipids)  Lipids are components of some enzyme systems.  Layers of fat in the subcutaneous layer, provides insulation and protection from cold. Body temperature maintenance is done by brown fat. ❖ Fatty acids A fatty acid is a carboxylic acid consisting of a long, straight and unbranched hydrocarbon (aliphatic) chain and a terminal carboxyl group especially any of those occurring as esters in fats and oils.  General properties • Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, from 14 to 20. • Fatty acids are usually derived from triglycerides or phospholipids. • Fatty acids are important dietary sources of fuel for animals because, when metabolized, they yield large quantities of ATP. Many cell types can use either glucose or fatty acids for this purpose. • Long-chain fatty acids cannot cross the blood–brain barrier (BBB) and so cannot be used as fuel by the cells of the central nervous system; however, free short chain fatty acids and medium-chain fatty acids can cross the BBB, in addition to glucose and ketone bodies. • Solubility:  Longer chains: more hydrophobic, less soluble.  Double bonds increase solubility. • Melting points:  Depend on chain length and saturation. Double bonds lead chain disorder and low melting temperature.  Unsaturated FAs are solids at Room Temperature. 9 Maesha Musarrat (Lipids)  Types of fatty acids According to the Length of the hydrocarbon Chain; fatty acids are of 4 types: I. Short-chain Fatty Acid Short-chain fatty acids (SCFAs), also referred to as volatile fatty acids (VFAs), are fatty acids with two to six carbon atoms. Free SCFAs can cross the blood-brain barrier via monocarboxylate transporters. II. Medium chain fatty acids Medium-chain fatty acids (MCFA) are fatty acids with aliphatic tails of 8 to 14 carbons. III. Long-chain fatty acids Long-chain fatty acids (LCFA) are fatty acids with aliphatic tails of 16 to 20 carbons. IV. Very long chain fatty acid A very long chain fatty acid (VLCFA) is a fatty acid with 22 or more carbons. According to the degree of unsaturation fatty acids are of two types: 10 Maesha Musarrat (Lipids) Saturated Fatty Acid Saturated fatty acids do not contain double bonds. e.g. Capric acid, Lauric acid, Myristic acid etc. Unsaturated fatty acids contain one or more double bonds Unsaturated Fatty Acid Monounsaturated Fatty Acid • • • Polyunsaturated Fatty Acid • Fatty acids with one double bond are monounsaturated (MUFA) e.g. Palmitoleaic acid, Oleic acid Fatty acids with 2 or more double bonds are collectivelv known as polyunsaturated fatty acids (PUFA). e.g. Linoleic acid, Linolenic acid, Arachidonic acid 11 Maesha Musarrat (Lipids) ❖ Essential fatty acids Essential fatty acids, or EFAs, are fatty acids that humans and other animals must ingest because the body requires them for good health but cannot synthesize them. Those not essential are non-essential fatty acids. Chemically, EFAs are polyunsaturated fatty acids, namelylinoleic acid & Iinolenic acid Arachidonic acid becomes essential if its precursor linoleic acid is not provided in the diet in sufficient amounts. The structures of EFA are given in the following table:  Omega-3 Fatty acid (2014, 2012, 2011) Omega-3 fatty acids—also called ω-3 fatty acids or n-3 fatty acids are polyunsaturated fatty acids (PUFAs) with a double bond (C=C) at the third carbon atom from the end of the carbon chain. The fatty acids have two ends, the carboxylic acid (-COOH) end, which is considered the beginning of the chain, thus "alpha", and the methyl (-CH3) end, which is considered the "tail" of the chain, thus "omega"; the double bond is at omega minus 3 (not dash 3). One way in which a fatty acid is named is determined by the location of the first double bond, counted from the methyl end, that is, the o ega ω-) or the n- end. However, the standard (IUPAC) chemical nomenclature system starts from the carbonyl end. 12 Maesha Musarrat (Lipids) The three types of omega-3 fatty acids involved in human physiology are αlinolenic acid (ALA) (found in plant oils), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) (both commonly found in marine oils). ALA o tai s ar o ato s, hereas EPA a d DHA are o sidered lo g- hai (LC) omega-3s because EPA contains 20 carbons and DHA contains 22. 13 Maesha Musarrat (Lipids)  Sources of Omega 3 Fatty acids ➢ Alpha-linolenic acid (ALA) is a type of Omega 3 fat found in plant foods which cannot be manufactured by the human body. Once consumed, ALAs can be converted into eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) but the conversion (which occurs primarily in the liver) is very limited, with reported rates of less than 15%. EPAs and DHAs are also typically found in seafood. ➢ ALA is present in plant oils, such as flaxseed, soybean, and canola oils . Chia seeds and black walnuts also contain ALA. ➢ DHA and EPA are present in fish, fish oils, and krill oils, but they are originally synthesized by microalgae, not by the fish. When fish consume phytoplankton that consumed microalgae, they accumulate the omega-3s in their tissues. ➢ The omega-3 content of fish varies widely. Cold-water fatty fish, such as salmon, mackerel, tuna, herring, and sardines, contain high amounts of 14 Maesha Musarrat (Lipids) long chain omega-3s ( EPA & DPA), whereas fish with a lower fat content— such as bass, tilapia and cod—as well as shellfish contain lower levels. ➢ The omega-3 content of fish also depends on the composition of the food that the fish consumes. Farmed fish usually have higher levels of EPA and DHA than wild-caught fish, but it depends on the food they are fed. An analysis of the fatty acid composition of farm-raised Atlantic salmon from Scotland showed that the EPA and DHA content significantly decreased between 2006 and 2015 due to the replacement of traditional marine ingredients in fish feed with other ingredients. ➢ Beef is very low in omega-3s, but beef from grass-fed cows contains somewhat higher levels of omega-3s, mainly as ALA, than that from grainfed cows. ➢ Some foods, such as certain brands of eggs, yogurt, juices, milk, and soy beverages, are fortified with DHA and other omega-3s. Since 2002, manufacturers have added DHA and arachidonic acid (the two most prevalent LC PUFAs in the brain) to most infant formulas available in the United States. Source: https://ods.od.nih.gov/factsheets/Omega3FattyAcidsHealthProfessional/#e n3  Functions of omega 3 fatty acids Cardiovascular disease (CVD) and CVD risk factors Higher dietary or plasma levels of omega-3s are associated with a lower risk of heart failure, coronary disease, and fatal coronary heart disease Recommendations from the Dietary Guidelines for Americans: The 2015–2020 Dietary Guidelines for Americans states that eating patterns that include seafood are associated with reduced risk of CVD. In addition, consuming about 8 ounces per week of a variety of seafood that provides about 250 mg per day EPA and DHA is associated with fewer cardiac deaths in both healthy individuals and those with preexisting CVD. 15 Maesha Musarrat (Lipids) Infant health and neurodevelopment High concentrations of DHA are present in the cellular membranes of the brain and retina, and DHA is important for fetal growth and development. The accumulation of DHA in the retina is complete by birth, whereas accumulation in the brain continues throughout the first 2 years after birth. Recommendations from the Dietary Guidelines for Americans: The 2015–2020 Dietary Guidelines for Americans states that women who are pregnant or breastfeeding should consume 8–12 ounces of seafood per week, choosing from varieties that are higher in EPA and DHA and lower in methyl mercury, such as salmon, herring, sardines, and trout. The American Academy of Pediatrics has similar advice for breastfeeding women, recommending intakes of 200–300 mg DHA per day by consuming one to two servings of fish per week to guarantee a sufficient amount of DHA in breast milk. Cancer prevention Researchers have hypothesized that higher intakes of omega-3s from either foods or supplements might reduce the risk of cancer due to their anti-inflammatory effects and potential to inhibit cell growth factors. Alzhei er’s disease, de e tia, a d cog itive fu ctio Diets high in DHA are associated with a reduced risk of cognitive decline, Alzhei er’s disease, a d de e tia. Be ause DHA is a esse tial o po e t of cellular membrane phospholipids in the brain might protect cognitive function by helping to maintain neuronal function and cell- membrane integrity within the brain. Age-Related Macular Degeneration (AMD) AMD is a major cause of vision loss among older adults. In most cases, severe vision loss is associated with advanced AMD, which consists of either central geographic atrophy (dry AMD, the most common form) or neovascular AMD (wet AMD . Based o DHA’s prese e as a stru tural lipid i reti al ellular e ra es and the beneficial effects of EPA-derived eicosanoids on retinal inflammation, neovascularization, and cell survival, researchers have suggested that these LC 16 Maesha Musarrat (Lipids) omega-3s have cytoprotective effects in the retina that may help prevent the development or progression of AMD. Rheumatoid arthritis Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. Its symptoms include pain, swelling, stiffness, and functional impairments. RA is typically treated with nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, and disease-modifying antirheumatic drugs. Due to their antiinflammatory effects, some scientists hypothesize that LC omega- s redu e so e of the s pto s of RA a d patie ts’ reliance on NSAIDs and corticosteroids. Other conditions The benefits of omega-3 supplementation are being investigated for several other conditions, including depression, inflammatory bowel disease, attention- deficit/ hyperactivity disorder (ADHD), childhood allergies, and cystic fibrosis.  Omega-6 fatty acid (2014, 2012, 2011) Omega-6 fatty acids—also called ω-6 fatty acids or n-6 fatty acids are polyunsaturated fatty acids (PUFAs), have their first double bond (C=C) at the 6th carbon atom from the methyl (-CH3) end of the carbon chain, which is considered the "tail" of the chain, thus "omega"; 17 Maesha Musarrat (Lipids) Omega-6 fatty acids help reduce inflammation, and some omega-6 fatty acids tend to promote inflammation. In fact, some studies suggest that elevated intakes of omega-6 fatty acids may play a role in complex regional pain syndrome. There are several different types of omega-6 fatty acids, and not all promote inflammation. Most omega-6 fatty acids in the diet come from vegetable oils, such as linoleic acid (LA), Linoleic acid is converted to gamma-linolenic acid (GLA) in the body. It can then break down further to arachidonic acid (AA). GLA is found in several plant-based oils, including evening primrose oil (EPO), borage oil, and black currant seed oil. GLA may actually reduce inflammation. Much of the GLA taken as a supplement is converted to a substance called DGLA that fights inflammation. Having enough of certain nutrients in the body (including magnesium, zinc, and vitamins C, B3, and B6) helps promote the conversion of GLA to DGLA. 18 Maesha Musarrat (Lipids)  Dietary sources of omega-6 fatty acids include: • • • • • • • • • • • • • • • • • • • • • • • • • • poultry eggs nuts cereals durum wheat whole-grain breads most vegetable oils grape seed oil evening primrose oil borage oil blackcurrant seed oil flax/linseed oil rapeseed or canola oil hemp oil soybean oil cottonseed oil sunflower seed oil corn oil safflower oil pumpkin seeds acai berry cashews pecans pine nuts walnuts spirulina 19 Maesha Musarrat (Lipids)  Functions of omega 6 fatty acids Diabetic neuropathy Some studies show that taking gamma linolenic acid (GLA) for 6 months or more may reduce symptoms of nerve pain in people with diabetic neuropathy. People who have good blood sugar control may find GLA more effective than those with poor blood sugar control. Rheumatoid arthritis (RA) Studies are mixed as to whether evening primrose oil (EPO) helps reduce symptoms of RA. Preliminary evidence suggests EPO may reduce pain, swelling, and morning stiffness, but other studies have found no effect. When using GLA for symptoms of arthritis, it may take 1 to 3 months for benefits to appear. It is unlikely that EPO would help stop progression of the disease. So joint damage would still occur. Allergies Omega-6 fatty acids from food or supplements, such as GLA from EPO or other sources, have a longstanding history of folk use for allergies. Women who are prone to allergies appear to have lower levels of GLA in breast milk and blood. However, there is no good scientific evidence that taking GLA helps reduce allergy symptoms. Well-conducted research studies are needed. Before you try GLA for allergies, work with your doctor to determine if it is safe for you. Then follow your allergy symptoms closely for any signs of improvement. Attention deficit/hyperactivity disorder (ADHD) Clinical studies suggest that children with ADHD have lower levels of EFAs, both omega-6s and omega-3s. EFAs are important to normal brain and behavioral function. Some studies indicate that taking fish oil (containing omega-3 fatty acids) may help reduce ADHD symptoms, though the studies have not been well designed. Most studies that used EPO have found it was no better than placebo at reducing symptoms. 20 Maesha Musarrat (Lipids) Breast cancer One study found that women with breast cancer who took GLA had a better response to tamoxifen (a drug used to treat estrogen-sensitive breast cancer) than those who took only tamoxifen. Other studies suggest that GLA inhibits tumor activity among breast cancer cell lines. There is some research suggesting that a diet rich in omega-6 fatty acids may promote breast cancer development. DO NOT add fatty acid supplements, or any supplements, to your breast cancer treatment regimen without your doctor's approval. Eczema Evidence is mixed as to whether EPO can help reduce symptoms of eczema. Preliminary studies showed some benefit, but they were not well designed. Later studies that examined people who took EPO for 16 to 24 weeks found no improvement in symptoms. If you want to try EPO, talk to your doctor about whether it is safe for you. High blood pressure (hypertension) Preliminary evidence suggests that GLA may help reduce high blood pressure, either alone or in combination with omega-3 fatty acids found in fish oil, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In one study, men with borderline high blood pressure who took 6g of blackcurrant oil had a reduction in diastolic blood pressure compared to those who took placebo. Another study examined people with intermittent claudication, which is pain in the legs while walking that is caused by blockages in the blood vessels. Those who took GLA combined with EPA had a reduction in systolic blood pressure compared to those who took placebo. More research is needed to see whether GLA is truly effective for hypertension. Menopausal symptoms EPO has gained popularity as a way to treat hot flashes associated with menopause. But so far studies have been inconclusive. 21 Maesha Musarrat (Lipids) Breast pain (mastalgia) Some evidence suggests that EPO may reduce breast pain and tenderness in people with cyclic mastalgia. It may also help reduce symptoms to a lesser extent in people with noncyclic mastalgia. However, it does not seem to be effective for severe breast pain. Multiple sclerosis (MS) EPO has been suggested as an additional treatment (along with standard therapy) for MS, although there is no scientific evidence that it works. People with MS who want to add EPO to their treatment regimens should talk with a health care provider. Osteoporosis Some studies suggest that people who do not get enough essential fatty acids (particularly EPA and GLA) are more likely to have bone loss than those with normal levels of these fatty acids. In a study of women over 65 with osteoporosis, those who took EPA and GLA supplements had less bone loss over 3 years than those who took placebo. Many of these women also experienced an increase in bone density. Premenstrual syndrome (PMS) Although most studies have found no effect, some women report relief of PMS symptoms when using GLA. The symptoms that seem to improve the most are breast tenderness and feelings of depression, as well as irritability and swelling and bloating from fluid retention. 22 Maesha Musarrat (Lipids)  Omega-6/Omega-3 ratio: (2011, 2009, 2008) Modern Western diets typically have ratios of omega-6 to omega-3 in excess of 10 to 1, some as high as 30 to 1; the average ratio of omega-6 to omega-3 in the Western diet is 15:1–16.7:1. Healthy ratios of omega-6:omega-3, according to some authors, range from 1:1 to 1:4. Other authors believe that a ratio of 4:1 (4 times as much omega-6 as omega3) is already healthy. The importance of the ratio of omega-6/omega-3 essential fatty acids: Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today's Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a low omega-6/omega-3 ratio) exert suppressive effects. ▪ In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. ▪ A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. ▪ The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2-3/1 suppressed inflammation in patients with rheumatoid arthritis, and ▪ a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. studies indicate that the optimal ratio may vary with the disease under consideration. [SOURCE: https://www.ncbi.nlm.nih.gov/pubmed/12442909] omega-6:omega-3 ratio has significant influence on the ratio and rate of production of eicosanoids, a group of hormones intimately involved in the body's inflammatory and homeostatic processes, which include the prostaglandins, leukotrienes, and thromboxanes, among others. Altering this ratio can change the 23 Maesha Musarrat (Lipids) body's metabolic and inflammatory state. In general, grass-fed animals accumulate more omega-3 than do grain-fed animals, which accumulate relatively more omega-6. Metabolites of omega-6 are more inflammatory (esp. arachidonic acid) than those of omega-3. This necessitates that omega-6 and omega-3 be consumed in a balanced proportion. [Source: https://en.wikipedia.org/wiki/Omega-3_fatty_acid] Ratios of omega-6: omega-3 in some foods Canola oil - 2:1, Walnut oil – 5:1, olive oil 13:1, English walnut – 4:1, pumpkin seeds-114:1, sunflower oil- 19:1 etc 24 Maesha Musarrat (Lipids) ❖ Level of different types of lipid in the human body: Total cholesterol levels: • • • Desirable: Below 200 mg/dL Borderline high: 200 to 239 mg/dL High: Above 240 mg/dL LDL cholesterol levels: • • • • • Optimal for people with heart disease or who are at high risk: Below 70 mg/dL Optimal for people at risk of heart disease: Below 100 mg/dL Optimal: 100 to 129 mg/dL Borderline high: 130 to 159 mg/dL High: 160 to 189 mg/dL HDL cholesterol levels: • • • Poor: Below 40 mg/dL Acceptable: 40 to 59 mg/dL Optimal: 60 or above mg/dL Triglyceride levels: • • • Optimal: Below 150 mg/dL Borderline high: 150 to 199 mg/dL High: Above 200 mg/dL 25 Maesha Musarrat (Lipids) ❖ Cholesterol: The word cholesterol is derived from the Ancient Greek hole (bile) and stereos (solid) followed by the chemical suffix ol for an alcohol, is an organic molecule. Cholesterol is found exclusively in animals; hence it is often called as animal sterol. The total body content of cholesterol in an adult man weighing 7Okg is about 140g i.e. around 2 g/kg body weight. Cholesterol is amphipathic in nature, since it possesses both hydrophilic and hydrophobic regions in the structure.  Structure of Cholesterol: 26 Maesha Musarrat (Lipids)  The Pathways of Cholesterol Metabolism: (2014, 2011, 2008) Plasma cholesterol concentrations are maintained by biosynthesis through the endogenous pathway and absorption of dietary and biliary cholesterol through the exogenous pathway. In the endogenous pathway, cholesterol is synthesized by the liver and extra hepatic tissues and secreted into plasma, whereas the intestine is the primary site of the exogenous pathway of dietary cholesterol uptake. Alteration of either pathway will affect the concentration of plasma cholesterol. Figure: The endogenous and exogenous pathways of cholesterol metabolism. HDL= high-density lipoprotein; VLDL= very-low-density lipoprotein; IDL= intermediate density lipoprotein; LDL= low-density lipoprotein; LDL-R= lowdensity lipoprotein receptor. 27 Maesha Musarrat (Lipids) ▪ Endogenous pathway: Cholesterol from the liver can be secreted into the bile or can be incorporated, as the free or esterified form, into lipoproteins, namely very-low-density lipoprotein (VLDL) and LDL, which are then secreted into plasma. Elevated levels of cholesterol in the liver will lead to an increased production of VLDL and/or LDL, as well as down-regulation of the LDL receptor. The increase in lipoprotein production and the decrease in LDL clearance can both lead to an elevation in plasma cholesterol level. Figure: Exogenous pathway of cholesterol metabolism. ACAT= acyl CoA: cholesterol acyltransferase; CE= cholesteryl ester; FC= free cholesterol. ▪ Exogenous pathway: Cholesterol is derived from bile and from dietary sources, which predominantly comprise animal and dairy food products. In the intestinal lumen, if the cholesterol is esterified, the ester is cleaved from the cholesterol moiety by 28 Maesha Musarrat (Lipids) pancreatic cholesteryl ester hydrolase, which is produced by the exocrine pancreas. Free cholesterol, along with other lipids and fat-soluble vitamins, is then solubilized into micelles and is subsequently absorbed by enterocytes by a mechanism that is not completely understood. After absorption, the free cholesterol is re-esterified to cholesteryl ester by acyl CoA:cholesterol acyltransferase (ACAT), and is packaged with other lipids into chylomicrons, which are secreted into the mesenteric lymph and ultimately into plasma. Once in circulation, chylomicrons are hydrolyzed by lipoprotein lipase at the endothelial surface of vessels and are reduced to chylomicron remnants. These chylomicron remnants can then be removed from the circulation by the liver or, if they are small enough, may be able to penetrate the endothelial surface of the arterial wall, where they may contribute to plaque formation. Figure: Exogenous and Endogenous pathway of cholesterol metabolism 29 Maesha Musarrat (Lipids) ▪ Reverse cholesterol pathway: Reverse cholesterol pathway refers to the process by which cholesterol is removed from the tissues and returned to the liver. HDL is the key lipoprotein involved in reverse cholesterol transport and the transfer of cholesteryl esters between lipoproteins. The smallest and most dense lipoprotein particle is HDL. HDL is formed through a maturation process where nascent HDL is secreted by the liver and intestine and proceeds through a series of conversions (known as the "HDL cycle") to attract cholesterol from cell membranes and free cholesterol to the core of the HDL particle. It has been suggested that the action of cholesteryl ester transfer protein transforms HDL into a TAG-rich particle that interacts with hepatic-triglyceride lipase. Cholesterol ester-rich HDL may also be taken up directly by the receptors in the liver. Another mechanism may be that cholesterol esters are delivered directly to the liver for uptake without catabolism of the HDL cholesterol particle. In relation to pathological change it has been accepted that higher levels of HDL are associated with lower levels of heart disease, therefore higher levels of HDL are considered to be protective. In contrast, it is accepted that other lipoproteins, including VLDL, IDL, LDL, and the remnant particles rendered in lipid processing, are highly atherogenic. The term "non-HDL cholesterol" has been adopted to describe this increased risk reflected in the lipid profile that may not be otherwise identified by simply examining the LDL alone. Non-HDL cholesterol therefore encompasses a broader indication of cardiovascular disease risk. 30 Maesha Musarrat (Lipids) Figure: Metabolism of Cholesterol  Diseases related to Cholesterol metabolism: (2014, 2011) In healthy individuals, the total plasma cholesterol is in the range of 150-200 mg/dl. In the new born, it is less than 100 mg/dl and rises to about 150 mg/dl within a year. There are two consequences of cholesterol metabolism disorder in the human body – A. Hypercholesterolemia B. Hypocholesterolemia 31 Maesha Musarrat (Lipids) A.Hypercholesterolemia: Increase in plasma cholesterol (> 200 mg/dl) concentration is known as hypercholesterolemia. Hypercholesterolemia is also called dyslipidemia. It causes many diseases. 1. Diabetes mellitus: Due to increased cholesterol synthesis since the availability of acetyl CoA is increased. 2. Hypothyroidism (myxedema): This is believed to be due to decrease in the high density lipoprotein (HDL) receptors on hepatocytes. 3. Obstructive jaundice: Due to an obstruction in the excretion of cholesterol through bile. 4. Nephrotic syndrome: Increase in plasma globulin concentration is the characteristic feature of nephrotic syndrome. Cholesterol elevation is due to increase in plasma lipoprotein fractions in this disorder. 5. Atherosclerosis: Atherosclerosis is characterized by deposition of cholesteryl esters and other lipids in the intima of the arterial walls often leading to hardening of coronary arteries and cerebral blood vessels. 6. High blood pressure: When the arteries become hardened and narrowed with cholesterol plaque and calcium, the heart has to strain much harder to pump blood through them. As a result, blood pressure becomes abnormally high. 7. Coronary heart disease: If the cholesterol level is too high, cholesterol can build up in the walls of arteries. This causes arteries to become narrowed, which slows the blood flow to the heart muscle. Reduced blood flow can result in angina (chest pain) or in a heart attack if a blood vessel gets blocked completely. 32 Maesha Musarrat (Lipids) 8. Stroke: Due to deposition of cholesterol, arteries that lead to the brain become narrowed and even blocked. If a vessel carrying blood to the brain is blocked completely, it can cause a stroke. 9. Peripheral Vascular Disease: High cholesterol is also linked to peripheral vascular disease. This refers to diseases of blood vessels outside the heart and brain. In this condition, cholesterol deposits build up along artery walls and affect blood circulation. This occurs mainly in arteries that lead to the legs and feet. B.Hypocholesterolemia: Hypocholesterolemia is defined as a total serum cholesterol level lower than 120 mg/dl. However, some authors suggest a cut-off level to be 160 mg/dl. The most common clinical situations related to hypocholesterolemia are given below – 1. Anemias: Hypocholesterolemia has been described in various types of chronic anemia which include: congenital dyserythropoietic anemia, congenital spherocytosis, sickle cell anemia, beta thalassemia, aplastic anemia, and sideroblastic anemia. Increased erythropoietic activity in various anemias is proposed as a mechanism that consumes plasma pool of cholesterol for the construction of cell membranes of the young erythrocytes. Low levels of serum cholesterol and other lipids suggested severe bone marrow failure and irresponsiveness to therapy in aplastic anemia patients. 2. Malabsorption: Hypocholesterolemia is observed in celiac disease. There was hypocholesterolemia in 35% of pediatric patients with celiac disease. Reduced intestinal lipolysis observed in pancreatitis also results with hypocholesterolemia. 3. Hyperthyroidism: Hyperthyroidism is associated with hypocholesterolemia characterized by a reduction in total cholesterol, HDL and LDL. There is an upregulation of LDL receptor gene expression as well as increased lipoprotein lipase activity that result with increased lipoprotein clearance from the plasma. Thyroid hormones stimulate cholesterol ester transfer protein, an enzyme that transports cholesterol esters from HDL to VLDL which is metabolized by 33 Maesha Musarrat (Lipids) lipoprotein lipase in adipose tissue and muscle. All of these factors promote a lower blood cholesterol level. 4. Infection, inflammation and sepsis: Transient hypocholesterolemia and hypertriglyceridemia are observed at the initial phase of bacterial infections of various origin. Hypocholesterolemia was reported in malaria infection and has the strongest positive predictive value (96%) among parameters for malaria diagnosis. Hypocholesterolemia is a typical laboratory finding in severe chronic hepatic insufficiency due to viral cirrhosis. It was found that serum cholesterol levels were low in tuberculosis infection and diet high in cholesterol helped the patients to recover from the disease. Patients develop hypocholesterolemia during sepsis. Hypocholesterolemia has been observed in several inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus and sarcoidosis. ❖ Membrane lipid: (2008, 2010) Membrane lipids are lipids involved in forming the structure of biological membranes – both the cell membrane and intracellular membranes – and in membrane function. A membrane lipid is a compound which belongs to a group of structurally similar to fats and oils which form the double-layered surface of all cells (lipid bilayer). These lipids are amphiphilic: they have one end that is soluble in water ('polar') and an ending that is soluble in fat ('nonpolar'). By forming a double layer with the polar ends pointing outwards and the nonpolar ends pointing inwards membrane lipids can form a 'lipid bilayer' which keeps the watery interior of the cell separate from the watery exterior. The arrangements of lipids and various proteins, acting as receptors and channel pores in the membrane, control the entry and exit of other molecules and ions as part of the cell's metabolism. 34 Maesha Musarrat (Lipids) Figure: Lipid bilayer  Types of membrane lipids: The three major classes of membrane lipids are a) Phospholipids, b) Glycolipids, and c) Cholesterol The structures of membrane lipids are given below – 35 Maesha Musarrat (Lipids) (a) Phospholipids: The major class of membrane lipids is the phospholipids. They are abundant in all biological membranes. Phospholipids are made from four components: one or more fatty acids, a platform to which the fatty acids are attached, a phosphate, and an alcohol attached to the phosphate. The fatty acid portion provides the hydrophobic barrier found in lipids, whereas the rest of the molecule has a hydrophilic property, enabling interaction with the aqueous environment. Phospholipids are built upon a foundation of glycerol, a three-carbon alcohol, or sphingosine. Phospholipids which are derived from glycerol are also known as phosphoglycerides, which consist of a glycerol backbone where two fatty acid chains and a phosphorylated alcohol are attached. The major phosphoglycerides come from phosphatidate through the formation of an ester bond between the phosphate group of phosphatidate and the hydroxyl group of one of several alcohols. Sphingosine is a phospholipid found in membranes that is not derived from glycerol. The backbone in sphingomyelin, however, is sphingosine, which is an amino alcohol which contains a long, unsaturated hydrocarbon chain. 36 Maesha Musarrat (Lipids) Figure: Types of Phospholipids 37 Maesha Musarrat (Lipids) (b) Glycolipids: Glycolipids are sugar-containing lipids. Glycolipids are typically composed of short, branched chains with less than 15 sugar units. The sugar could be either glucose or galactose. Figure: Structure of Glycolipid (c) Cholesterol: Cholesterol is a steroid built from four linked hydrocarbon rings. A hydrocarbon tale is at one end of the steroid while a hydroxyl group is attached to the other end. Figure: Structure of cholesterol 38 Maesha Musarrat (Lipids)  Functions of membrane lipids: The functions of membrane lipids are – • Working as diffusion barrier • Controlling movement of Specific molecules • Maintain shape of the cell ❖ Phospholipids: (2012) Phospholipids are esters of fatty acid with alcohol attached to phosphoric acid with or without nitrogen base. These are the derivatives of phosphatidic acid in which the phosphate is esterified with the hydroxyl group (-OH) of a suitable alcohol. In other words, phospholipids are complex or compound lipids, composed of fatty acids, glycerol, phosphoric acid and in most cases a nitrogen base. Phospholipid = Fatty acid + Alcohol + Phosphoric acid + Nitrogen base  Location: Phospholipids are present in biological membranes like cell membranes, mitochondrial membrane in brain, nerve tissue and muscle.  Amphipathic nature of phospholipids: (2010) An amphiphile is a term describing a chemical compound possessing both hydrophilic (water-loving, polar) and lipophilic (fat-loving) properties. The structure of the phospholipid molecule generally consists of two hydrophobic fatty acid "tails" and a hydrophilic "head" consisting of a phosphate group. The phospholipid head contains a negatively charged phosphate group and glycerol; it is hydrophilic (attracted to water). The phospholipid tails usually consists of 2 long fatty acid chains; they are hydrophobic and are repelled by water. When placed in water, phospholipids form a variety of structures depending on the specific properties of the 39 Maesha Musarrat (Lipids) phospholipid with tails typically aggregating to minimize interactions with water molecules. These specific properties allow phospholipids to play an important role in the phospholipid bilayer. In biological systems, the phospholipid often occur with other molecules (e.g., proteins, glycolipids, sterols) in a bilayer such as a cell membrane. Lipid bilayers occur when hydrophobic tails line up against one another, forming a membrane of hydrophilic heads on both sides facing the water. Figure: Amphipathic nature of Phospholipid  Classification of Phospholipids: (2010) Phospholipids are two classes of phospholipids A. Glycerophospholipids (or phosphoglycerides) that contain glycerol as the alcohol. B. Sphingophospholipids (or sphingomyelins) that contains phingosinea s the alcohol. 40 Maesha Musarrat (Lipids) A. Glycerophospholipids: Glycerophospholipids are the major lipids that occur in biological membranes. They consist of glycerol 3-phosphate esterified at its C1 and C2 with fatty acids. Usually, C1 contains a saturated fatty acid while C2 contains an unsaturated fatty acid. 1. Phosphatidic acid : This is the simplest phospholipid. lt does not occur in good concentration in the tissues. Basically, phosphatidic acid is an intermediate in the synthesis of triacylglycerols and phospholipids. The other glycerophospholipids containing different nitrogenous bases or other groups may be regarded as the derivatives of phosphatidic acid. 2. Lecithins (phosphatidylcholine): These are the most abundant group of phospholipids in the cell membranes. Chemically, lecithin (Greek : lecithos-egg yolk) is a phosphatidic acid with choline as the base. Phosphatidylcholines represent the storage form of body's choline. i. ii. Dipalmitoyl lecithin: It is an important phosphatidylcholine found in lungs. lt is a surface active agent and prevents the adherence of inner surface of the lungs due to surface tension. Respiratory distress syndrome in infants is a disorder characterized by the absence of dipalmitoyl lecithin. Lysolecithin: It is formed by removal of the fatty acid either at C1 or C2 of lecithin. 3. Cephalins (phosphatidylethanolamine): Ethanolamine is the nitrogenous base present in cephalins. Thus, lecithin and cephalin differ with regard to the base. 4. Phosphatidylinositol: The steroisomer myo-inositol is attached to phosphatidic acid to give phosphatidylinositol (Pl). This is an important component of cell membranes. The action of certain hormones (e.g. oxytocin, vasopressin) is mediated through Pl. 5. Phosphatidylserine: The amino acid serine is present in this group of glycerophospholipids. Phosphatidylthreonine is also found in certain tissues. 41 Maesha Musarrat (Lipids) 42 Maesha Musarrat (Lipids) 6. Plasmalogens: When a fatty acid is attached by an ether linkage at C1 of glycerol in the glycerophospholipids, the resultant compound is plasmalogen. Phosphatidalethanolamine is the most imoortant which is similar in structure to phosphatidylethanolamine but for the ether linkage (in place of ester). An unsaturated fatty acid occurs at C1. Choline, inositol and serine may substitute ethanolamine to give other plasmalogens. 7. Cardiolipin : lt is so named as it was first isolated from heart muscle. Structurally, a cardiolipin consists of two molecules of phosphatidic acid held by an additional glycerol through phosphate groups. lt is an important component of inner mitochondrial membrane. Cardiolipin is the only phosphoglyceride that possesses antigenic properties. B. Sphingomyelins: Sphingosine is an amino alcohol present in sphingomyelins (sphingophospholipidh). They do not contain glycerol at all. Sphingosine is attached by anamide linkage to produce ceramide. The alcohol group of sphingosine is bound to phosphorylcholine in sphingomyelin structure. Sphingomyelins are important constituents of myelin and are found in good quality in brain and in nervous system.  Functions of Phospholipids: Phospholipids constitute an important group of compound lipids that perform a wide variety of functions. Such as 1. In association with proteins, phospholipids form the structural components of membranes and regulate membrane permeability. 2. Phospholipids (lecithin, cephalin and cardiolipin) in the mitochondria are responsible for maintaining the conformation of electron transport chain components, and thus cellular respiration. 3. Phospholipids participate in the absorption of fat from the intestine. 43 Maesha Musarrat (Lipids) 4. Phospholipids are essential for the synthesis of different lipoproteins, and thus participate in the transport of lipids. 5. Accumulation of fat in liver (fatty liver) can be prevented by phospholipids, hence they are regarded as lipotropic factors. 6. Arachidonic acid, an unsaturated fatty acid liberated from phospholipids, serves as a precursor for the synthesis of eicosanoids (prostaglandins, prostacyclins, thromboxanes etc.). 7. Phospholipids participate in the reverse cholesterol transport and thus help in the removal of cholesterol from the body. 8. Phospholipids act as surfactants (agents lowering surface tension). For instance, dipalmitoyl phosphatidylcholine is an important lung surfactant. Respiratory distress syndrome in infants is associated with insufficient production of this surfactant. 9. Cephalins, an important group of phospholipids participate in blood clotting. 10. Phospholipids (phosphatidylinositol) are involved in signal transmission across membranes. ❖ Ecosanoids: (2014, 2013, 2009) The ord e osa oid is deri ed fro the Greek ord ei osa hi h ea s twenty. Ecosanoids are 20 carbon compounds, derived from arachidonic acid and some other 20 carbon polyunsaturated fatty acids. Ecosanoids are – • • • • • Prostaglandins (PG) Prostacyclins (PGI) Thromboxanes (TX) Leukotrienes (LT) Lipoxins (LX) 44 Maesha Musarrat (Lipids) These molecules almost always act on the cells that produce them or on neighboring cells i.e. over short distances and time periods and therefore can be classified as autocrine or paracrine hormones. Ecosanoids are also known as local hormones. They exert complex control over many bodily systems, mainly in inflammation or immunity, and as messengers in the central nervous system.  Ecosa oids are Local Hor o es : 2009 The eicosanoids are considered "local hormones". They have specific effects on target cells close to their site of formation. Local hormones are secreted into the interstitial fluid and they act locally in two ways. Some hormones act on the neighboring cells and are known as paracrine hormones and some hormones act on the cells from which they were secreted, they are autocrine hormones. Physiologically and pathologically, eicosanoids are local hormones.They are synth esized and exert their biological actions in the same tissue. The specific effect of each eicosanoid depends on sequential enzymatic machinery in a specific cell, yielding a specific eicosanoid, exerting its distinct function. They act on cells close to their site of production. Eicosanoids also rapidly break down, so they are not able to travel very far. Therefore, they are released by most cells, act on that same cell or nearby cells (i.e., they are autocrine and paracrine mediators), and then are rapidly inactivated. From the above discussion it can be concluded that the eicosanoids are considered "local hormones" as • They have specific effects on target cells close to their site of formation. • They are rapidly degraded, so they are not transported to distal sites within the body. 45 Maesha Musarrat (Lipids)  Major pathways of eicosanoids metabolism: (2012) There are two major pathways of eicosanoid metabolism. These are – 1.Cyclic pathway 2.Linear pathway 1.Cyclic pathway: (Role of Cyclooxygenase) 2008 In cyclic pathway production of prostaglandins, prostacyclins, and thromboxanes take place from arachidonic acid. Cyclooxygenase enxyme acts in this cycle. Prostaglandin H2 Synthase (PGH2 synthase) catalyzes the committed step in the li path a that leads to produ tio of prostagla di s, prosta li s, & thromboxanes. Different cell types convert PGH2 to different compounds. Prostaglandin H2 Synthase is a heme-containing dioxygenase, bound to endoplasmic reticulum membranes. It exhibits two catalytic activities, Cyclooxygenase and Peroxidase. The enzyme expressing both activities is sometimes referred to as Cyclooxygenase (COX). The interacting cyclooxygenase and peroxidase reaction pathways are complex. A peroxide (such as that generated later in the reaction sequence) oxidizes the heme iron. The oxidized heme accepts an electron from a nearby tyrosine residue (Tyr385). The resulting tyrosine radical is proposed to extract a hydrogen atom from arachidonate, generating a radical species that reacts with O2. The signal molecule NO (nitric oxide) may initiate prostaglandin synthesis by reacting with superoxide anion (O2-) to produce peroxynitrite, which oxidizes the heme iron enabling electron transfer from the active site tyrosine. Prostaglandin synthesis in response to some inflammatory stimuli is diminished by inhibitors of Nitric Oxide Synthase. 46 Maesha Musarrat (Lipids) Figure: Cyclic pathway of ecosanoid metabolism Two isoforms of PGH2 Synthase are designated COX-1 and COX-2 (Cyclooxygenase 1 & 2). COX-1 is constitutively expressed at low levels in many cell types. COX-2 expression is highly regulated. Transcription of the gene for COX-2 is stimulated by growth factors, cytokines, and endotoxins COX-2 expression may be enhanced by cAMP, and in many cells PGE2 produced as a result of COX-2 activity itself leads to changes in cAMP levels. Though both cyclooxygenase isoforms catalyze PGH2 formation, differing localization within a cell, and localization of enzymes that convert PGH2 into particular prostaglandins or thromboxanes, may result in COX-1 and COX-2 yielding different ultimate products. COX-1 is essential for thromboxane formation in blood platelets, and for maintaining integrity of the gastrointestinal epithelium. Inflammation is 47 Maesha Musarrat (Lipids) associated with up-regulation of COX-2 and increased formation of particular prostaglandins. COX-2 levels increase in inflammatory diseases such as arthritis. Increased COX-2 expression is seen in some cancer cells. Angiogenesis (blood vessel development), which is essential to tumor growth, requires COX-2. Overexpression of COX-2 leads to increased expression of VEGF (vascular endothelial growth factor). Regular use of NSAIDs has been shown to decrease the risk of developing colorectal cancer. 2.Linear pathway: (Role of Lipooxygenase) 2008 In linear pathway, leukotrienes are produced from arachidonic acid. The first step of the linear pathway for synthesis of leukotrienes is catalyzed by lipoxygenase. Mammalian organisms have a family of lipoxygenase enzymes that catalyze oxygenation of various polyunsaturated fatty acids at different sites. Many of the products have signal roles. For example, 5-Lipoxygenase, found in leukocytes, catalyzes conversion of arachidonate to 5-HPETE (5-hydroperoxyeicosatetraenoic acid). 5-HPETE is converted to leukotriene-A4, which in turn may be converted to various other leukotrienes. A non-heme iron is the prosthetic group of ipoxygenase enzymes. Ligands to the iron include 4 histidine nitrogen atoms and the C-terminal carboxylate oxygen. The arachidonate substrate binds in a hydrophobic pocket, adjacent to the catalytic iron atom. O2 is thought to approach from the opposite side of the substrate than the side facing the iron, for a stereospecific reaction. The reaction starts with extraction of a hydrogen from arachidonate, with transfer of the electron to the iron, reducing it from Fe3+ to Fe2+. The fatty acid radical reacts with O2 to form a hydroperoxy fatty acid. Which hydrogen is extracted, & the position of the resulting hydroperoxy group, varies with different lipoxygenases. Additional reactions then yield the various leukotrienes. Leukotrienes have roles in inflammation. They are produced in areas of inflammation in blood vessel walls as part of the pathology of atherosclerosis. Leukotrienes are also implicated in asthmatic constriction of the bronchioles. 48 Maesha Musarrat (Lipids) Figure: linear pathway of ecosanoid metabolism ❖ Enterohepatic circulation of Bile acids and Bile salts: (2010) In an enterohepatic cycle, a substance is secreted by the liver into the bile, passes into the intestine and is taken up again into the blood, either by passive diffusion across cell membranes or by active transport. Since blood drained from the intestines feeds into the portal vein, the substance will return to the liver, where it may be captured by liver cells and once again secreted into the bile. The enterohepatic circulation of bile salts is the recycling of bile salts between the small intestine and the liver. The total amount of bile acids in the body, primary or 49 Maesha Musarrat (Lipids) secondary, conjugated or free, at any time is defined as the total bile acid pool. In healthy people, the bile acid pool ranges from 2 to 4 g. The enterohepatic circulation of bile acids in this pool is physiologically extremely important. By cycling several times during a meal, a relatively small bile acid pool can provide the body with sufficient amounts of bile salts to promote lipid absorption. In a light eater, the bile acid pool may circulate 3 to 5 times a day, in a heavy eater; it may circulate 14 to 16 times a day. The conjugated bile salts synthesized in the liver accumulate in gall bladder. From there they are secreted into the small intestine where they serve as emulsifying agents for the digestion and absorption of fats and fat soluble vitamins. A large portion of the bile salts (primary and secondary) are reabsorbed and returned to the liver through portal vein. Thus the bile salts are recycled and reused several times in a day. This is the mechanism of enterohepatic circulation. About 15-30 g of bile salts are secreted into the intestine each day and reabsorbed. However, a small portion of about 0.5 g/day is lost in the feces. An equal amount (0.5 g/day)i s synthesized in liver to replace the lost bile salts. The fecal excretion of bile salts is the only route for the removal of cholesterol from the body. 50 Maesha Musarrat (Lipids) Bile salts are recycled out of the small intestine in four ways: (1) passive diffusion along the small intestine (plays a relatively minor role); (2) carrier-mediated active absorption in the terminal ileum (the most important absorption route); (3) de-conjugation to primary bile acids before being absorbed either passively or actively; (4) conversion of primary bile acids to secondary bile acids with subsequent absorption of deoxycholic acid. 51 Maesha Musarrat (Lipids) ❖ The rate limiting step in bile acid synthesis: (2012) The bile acids possess 24 carbon atoms, 2 or 3 hydroxyl groups in the steroid nucleus and a side chain ending in carboxyl group. The bile acids are amphipathic in nature since they possess both polar and non-polar groups. They serve as emulsifying agents in the intestine and actively participate in the digestion and absorption of lipids. Synthesis of two primary bile acids – cholic acid (CA) and chenodeoxycholic acid (CDCA) from cholesterol which is catalyzed by the 7αhydroxylase enzyme is the rate limiting step in bile acid synthesis. 52 Maesha Musarrat (Lipids) Figure: Outline of bile acid synthesis (*- primary bile acids, **- secondary bile acids) The synthesis of primary bile acids takes place in the liver and involves a series of reactions. The step catalysed by 7 a-hydroxylase is inhibited by bile acids and this is the rate Iimiting reaction. Cholic acid and chenodeoxycholic acid are the primary bile acids and the former is found in the largesat mount in bile. On conjugation with glycine or taurine, conjugated bile acids (glycocholic acid, taurocholic acid etc.) are formed which are more efficient in their function as surfactants. In the bile, the conjugated bile acids exist as sodium and potassium salts which are known as bile salts. In the intestine a portion of primary bile acids undergoes deconjugation and dehydroxylation to form secondary bile acids (deoxycholic acid and lithocholic acid). These reactions are catalyzed by bacterial enzymes in the intestine. 53 Maesha Musarrat (Lipids) ❖ Prostaglandins: Prostaglandins are 20-carbon hydroxyl fatty acids containing a five-membered ring. These are widely distributed in lungs, kidney, thyroid, spleen, brain, iris, endometrium etc. The dietary precursor of the prostaglandins is the essential fatty acid, linoleic acid. It is elongated and desaturated to arachidonic acid, the immediate precursor of the prostaglandins. 54 Maesha Musarrat (Lipids) Figure: Prostaglandins with substituent groups and structures 55 Maesha Musarrat (Lipids)  Structure of Prostaglandins: Prostaglandins are derivatives of a hypothetical 2O-carbon fatty acid namely prostanoic acid hence known as prostanoids. This has a cyclopentane ring (formed by carbon atoms 8 to 12) and two side chains, with carboxyl group on one side. Prostaglandinds differ in their structure due to substituent group and double bond on cyclopentane ring. The different prostaglandins are given in the above figure.  Synthesis of Prostaglandins: Arachidonic acid (5, 8, 11, 14 –eicosatetraenoic acid) is the precursor for the most of the prostaglandins in humans. The biosynthesis of prostaglandins was described by scene Bregstrom and Bengt Samulsson in 1960. It occurs in the endoplasmic reticulum in the following stages – First stage – Release of arachidonic acid from membrane bound phospholipids by phospholipaseA2 . This reaction occurs due to a specific stimuli by hormones such as epinephrine or bradykinin. Second stage – Oxidation and cyclization of arachidonic acid to PGG2 which is then converted to PGH2 by a reduced glutathione dependent peroxidase. Third stage – PGH2 serves as the immediate precursor for the synthesis of a number of prostaglandins, including prostacyclins and thrombosis. The a o e path a is k o as cyclic pathway of arachidonic acid . 56 Maesha Musarrat (Lipids) Figure: Overview of biosynthesis of prostaglandins and related compounds (5-HPETE-5-Hydroxyperoxycicosatetraenoic acid; PG-Prostaglandins; PGI2Prostacyclin I2, TXA2-Thromboxane A2)  Biochemical Functions of Prostaglandins: (2010) Prostaglandins act as local hormones in their function. They are produced in almost all the tissues. They are degraded to inactive products at the site of their production instead of remain stored. Prostaglandins are involved in a variety of biological functions. The actions of prostaglandins differ in different tissues. Sometimes prostaglandins bring about opposing actions in the same tissue. 57 Maesha Musarrat (Lipids) Over production of prostaglandins result in many symptoms which include pain, fever, nausea, vomiting and inflammation. The biochemical functions of prostaglandins are described below – 1. Regulation of blood pressure: The prostaglandins (PGE, PGA and PGl2) are vasodilator in function. This results in increased blood flow and decreased peripheral resistance to lower the blood pressure. Prostaglandins serve as agents in the treatment of hypertension. 2. Inflammation: The prostaglandins PGE1 and PGE2 induce the symptoms of inflammation (redness, swelling, edema etc.) due to arteriolar vasodilation. This led to the belief that prostaglandins are natural mediators of inflammatory reactions of rheumatoid arthritis (involving joints), psoriasis (skin), conjunctivitis (eyes) etc. Corticosteroids are frequently used to treat these inflammatory reactions, since they inhibit prostaglandin synthesis. 3. Reproduction: Prostaglandins have widespread applications in the field of reproduction. PGE2 and PGF2 are used for the medical termination of pregnancy and induction of Iabor. Prostaglandins are administered to cattle to induce estrus and achieve better rate of fertilization. 4. Pain and Fever: lt is believed that pyrogens (fever producing agents) promote prostaglandin biosynthesis leading to the formation of PGE2 in the hypothalamus, the site of regulation of body temperature. PGE2 along with histamine and bradykinin cause pain. Migraine is also due to PGE2. Aspirin and other non-steroical drugs inhibit prostaglandin synthesis and thus control fever and relieve pain. 58 Maesha Musarrat (Lipids) 5. Regulation of gastric secretion: In general, prostaglandins (PGE) inhibit gastric secretion. Prostaglandins are used for the treatment of gastric ulcers. However, prostaglandins stimulate pancreatic secretion and increase the motility of intestine which often causes diarrhea. 6. Influence on immune system: Macrophages secrete PGE which decreases the immunological functions of B-and T –lymphocytes. 7. Effect on respiratory function: PGE is a bronchodilator whereas PGF acts as a constrictor of bronchial smooth muscles. Thus, PGE and PGF oppose the actions of each other in the lungs. PGE1 and PGE2 are used in the treatment of asthma. 8. Influence on renal function: PGE increases glomerular filtration rate (GFR) and promotes urine output. Excretion of Na+ and K+ is also increased by PGE. 9. Effects on metabolism: Prostaglandins influence certain metabolic reactions, probably through the mediation of cAMP. PGE decreases lipolysis, increases glycogen formation and promotes calcium mobilization from the bone. 10. Platelet aggregation and Thrombosis: The prostaglandins, namely prostacyclins (PGI2), inhibit platelet aggregation. On the other hand, thromboxanes (TXA2) and prostaglandin E2 promote platelet aggregation and blood clotting that might lead to thrombosis. PGl2, produced by endothelial cells lining the blood vessels, prevents the adherence of platelets to the blood vessels. TXA2 is released by the platelets and is responsible for their spontaneous aggregation when the platelets come in contact with foreign surface, collagen or thrombin. Thus, prostacyclins and thromboxanes are antagonists in their action. In the overall effect PGl2 acts as a vasodilator, while 59 Maesha Musarrat (Lipids) TXA2 is a vasoconstrictor. The balance between PGI2 and TXA2 is important in the regulation of hemostasis and thrombosis. ❖ NSAIDs: (2010) NSAIDs mean Non-Steroidal Anti-Inflammatory Drugs. NSAIDs are also known as anti-inflammatories. According to U.S Food and Drug Administration (FDA), NSAIDs are a group of drugs used to temporarily relieve pain and inflammation. They work by blocking the production of prostaglandins, or chemicals believed to be associated with pain and inflammation. NSAIDs temporarily relieve pain (in pain like headache and period pain), reduce inflammation or swelling (in conditions like arthritis and muscle and bone injuries) and lower a raised temperature.  Classification of NSAIDs: NSAIDs can be classified based on their chemical structure or mechanism of action. Older NSAIDs were known long before their mechanism of action was elucidated and were for this reason classified by chemical structure or origin. Newer substances are more often classified by mechanism of action. Salicylates • Aspirin (acetylsalicylic acid) • Diflunisal (Dolobid) • Salicylic acid and other salicylates • Salsalate (Disalcid) Propionic acid derivatives • Ibuprofen • Dexibuprofen • Naproxen 60 Maesha Musarrat (Lipids) • Fenoprofen • Ketaprofen • Dexketoprofen • Flurbiprofen • Oxaprozin • Loxoprofen Acetic acid derivatives • Indomethacin • Tolmetin • Sulindac • Etodolac • Ketorolac • Diclofenac • Aceclofenac • Nabumetone (drug itself is non-acidic but the active, principal metabolite has a carboxylic acid group) Enolic acid (Oxicam) derivatives • Piroxicam • Meloxicam • Tenoxicam • Droxicam • Lornoxicam 61 Maesha Musarrat (Lipids) • Isoxicam (withdrawn from market 1985) • Phenylbutazone (Bute) Anthranilic acid derivatives (Fenamates) The following NSAIDs are derived from fenamic acid. which is a derivative of anthranilic acid, which in turn is a nitrogen isosterei of salicylic acid, which is the active metabolite of aspirin. • Mefenamic acid • Meclofenamic acid • Flufenamic acid • Tolfenamic acid Selective COX-2 inhibitors (Coxibs) • Celecoxib (FDA alert) • Parecoxib FDA withdrawn, licensed in the EU • Lumiracoxib TGA cancelled registration • Etoricoxib not FDA approved, licensed in the EU • Firocoxib used in dogs and horses Sulfonanilides • Nimesulide (systemic preparations are banned by several countries for the potential risk of hepatotoxicity) Others • • Clonixin Licofelone acts by inhibiting LOX (lipooxygenase) & COX and hence known as 5-LOX/COX inhibitor 62 Maesha Musarrat (Lipids) • H-harpagide in Figwort or Devil's Claw  Most Common Types of NSAIDs: The four NSAIDs most often used to treat many types of back and neck pain are: • Aspirin (brand names include Bayer, Bufferin, and Ecotrin, St. Joseph) • Ibuprofen (Advil, Motrin) • Naproxen (Aleve, Anaprox DS, Naprosyn) • Celecoxib (Celebrex)  Other Forms of NSAIDs: In addition to the above, NSAIDs come in forms other than those taken by mouth. For example: • Ketorolac can be given as an intravenous, intramuscular, or intranasal drug, making it useful after surgery or if the patient cannot eat. • Diclofenac is available topically as a gel (Voltaren), patch (Flector), or solution (Pennsaid). The medication is applied directly to the area of pain. Topical forms reduce gastrointestinal and other potential side effects of NSAIDs.  Medical uses of NSAIDs: NSAIDs are usually used for the treatment of acute or chronic conditions where pain and inflammation are present. NSAIDs are generally used for the symptomatic relief of the following conditions: • Osteoarthristis • Rheumatoid arthritis • Mild-to-moderate pain due to inflammation and tissue injury • Low back pain 63 Maesha Musarrat (Lipids) • Inflammatory arthropathies • Tennis elbow • Headache • Migraine • Acute gout • Dysmenorrhoea (menstrual pain) • Metastic bone pain • Postoperative pain • Muscle stiffness and pain due to Parkinso ’s disease • Pyrexia (fever) • Ileus • Renal colic • • They are also given to neonate infants whose ductus arteriosus is not closed within 24 hours of birth Macular edema  Mechanism of action of NSAIDs: Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both the cyclooxygenase-1(COX-1) and cyclooxygenase-2(COX2) isoenzymes. This inhibition is competitively reversible as opposed to the mechanism of aspirin, which is irreversible inhibition. COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid. Prostaglandins act as messenger molecules in the process of inflammation. This mechanism of 64 Maesha Musarrat (Lipids) action was elucidated by John Vane (1927–2004), who received a Nobel Prize for his work. Prostaglandins are a family of chemicals that are produced by the cells of the body and have several important functions. They promote inflammation that is necessary for healing, but also results in pain and fever; support the blood clotting function of platelets; and protect the lining of the stomach from the damaging effects of acid. Prostaglandins are produced within the body's cells by the enzyme cyclooxygenase (COX). There are two COX enzymes, COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever. However, only COX-1 produces prostaglandins that support platelets and protect the stomach. Nonsteroidal anti-inflammatory drugs (NSAIDs) block the COX enzymes and reduce prostaglandins throughout the body. As a consequence, ongoing inflammation, pain, and fever are reduced. Since the prostaglandins that protect the stomach and support platelets and blood clotting also are reduced, NSAIDs can cause ulcers in the stomach and promote bleeding.  Antipyretic activity of NSAIDs: NSAIDS have antipyretic activity and can be used to treat fever. Fever is caused by elevated levels of prostaglandins E2, which alters the firing rate of neurons within the hypothalamus, that control thermoregulation. Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PEG2) within the hypothalamus. PEG2 signals to the hypothalamus to increase the body's thermal set point. Ibuprofen has been shown more effective as an antipyretic than paracetamol (acetaminophen). Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D & E. 65 Maesha Musarrat (Lipids)  Risks associated with using NSAIDs: There are risks associated with all pain relievers. NSAIDs should be used with caution, especially by people over the age of 65, those at risk of stomach or heart problems, or those with asthma. • Gastrointestinal problems The most common risk of standard NSAIDs is that they can cause ulcers and other problems in esophagus, stomach, or small intestine. • High Blood Pressure and Kidney Damage NSAIDs reduce the blood flow to the kidneys, which makes them work more slowly. When kidneys are not working well, fluid builds up in the body. The more fluid in bloodstream, the higher blood pressure. • Allergic Reactions NSAIDs can also cause extreme allergic reactions, especially in people with asthma, sinus problems or nasal polyps. • Photosensitivity Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. • During pregnancy NSAIDs are not recommended during pregnancy, particularly during the third trimester. While NSAIDs as a class are not direct teratogens, they may cause premature closure of the fetal ductus arteriosus. Additionally, they are linked with premature birth and miscarriage. 66 Maesha Musarrat (Lipids) ❖ COX-1 and COX-2: (2014, 2009) The full for of COX is C loo ge ase. It is a e z e. Cyclooxygenase (COX) is responsible for the formation of prostanoids. The three main groups of prostanoids are prostaglandins, prostacyclins, and thromboxanes. Therefore, cyclooxygenase is also known as prostaglandin-endoperoxide synthase (PTGS). In the 1990, researchers discovered that two different COX isoenzymes are existed. They are – a. COX-1 and b. COX-2 While both COX-1 and COX-2 convert arachidonic acid to prostaglandin, resulting in pain and inflammation, their other functions make inhibition of COX-1 undesirable while inhibition of COX-2 is considered desirable.  COX-1: COX-1 is a constitutive enzyme because it is produced by a cell under all types of physiological conditions. The amount at which constitutive enzymes are produced remain constant without regard of substrate concentration and physiological demand. Location: COX-1 is commonly found in the kidney, stomach and platelets. Function: COX-1 play important role in housekeeping such as it protects gastric mucosa, regulate gastric acid and maintain normal functions of kidney and platelet by stimulating prostaglainds. 67 Maesha Musarrat (Lipids) Production: The stimulation of COX-1 enzyme is done on a continuous basis by the body. Usefulness: COX-1 enzymes are protective in nature and therefore are useful for the body. So there is no need to inhibit them. Inhibition: Nonsteriodial antiinflammatory drugs inhibit COX-1. 68 Maesha Musarrat (Lipids)  COX-2: COX-2 is an inducible enzyme as it is produced under certain specific conditions like inflammation. Location: COX-2 is located in macrophages, leukocytes and fibroblasts. Function: COX-2 is involved in the synthesis of prostaglandins that causes pain and inflammation in the body. Production: COX-2 enzyme remain absent at normal condition and produced only at the time of need. The stimulation of COX-2 enzymes is dependent upon cytokines. Usefulness: COX-2 enzyme plays an important role in inflammation and pyrexia. So it is desirous to inhibit COX-2 enzyme Inhibition: There are different types of drugs that are used to inhibit COX-2 enzyme including Celecoxib, Nonsteriodial antiinflammatory drugs. 69 Maesha Musarrat (Lipids) 70 Maesha Musarrat (Lipids) ❖ Diets rich in Marine lipids: (2012) Marine lipid oils are omega-3 fatty acids. They are derived from the body oils of deep cold-water fish. They reduce the risk of atherosclerosis and cancer. Marine Lipid Oils (Omega-3 Fatty Acids) prevent blood platelets from sticking together (makes the blood less sticky); thins the blood and improves blood flow. They lower bad cholesterol and triglycerides. They help prevent heart attacks and strokes; lower blood pressure; enhance the immune system. They help prevent depression; offer protection against migraines and kidney disease. They reduce the signs and symptoms of psoriasis, eczema, and rheumatoid arthritis. Marine lipid oils (omega-3 fatty acids) keep the skin, hair and nails healthy. The mechanisms of decrease in cholesterol, prostaglandin and leukotriene level by marine lipids are described below -  Decrease cholesterol level: Diets rich in marine lipids are a good source of omega-3 fatty acids. Omega-3 fatty acids are poly unsaturated fatty acids. They reduce the cholesterol level because they help in the esterification of cholesterol present in high density lipoprotein (HDL). Poly unsaturated fatty acid is invariably required for forming lecithin. Long chain fatty acid tends to increase the cholesterol level. Short chain and medium fatty acids neither decrease nor increase cholesterol level. Poly unsaturated fatty acids increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL). Omega-3 fatty acid inhibits the biosynthesis of very-low-density lipoproteins (VLDL) and triglycerides in the liver.  Decrease prostaglandin levels: Prostaglandins are 20-carbon hydroxyl fatty acids containing a five-membered ring. These are widely distributed in lungs, kidney, thyroid, spleen, brain, iris, endometrium etc. The prostaglandins PGE1 and PGE2 induce the symptoms of inflammation (redness, swelling, edema etc.). Diets rich in marine lipids can decrease prostaglandin level in the body. 71 Maesha Musarrat (Lipids) Diets rich in marine lipids are a good source of omega-3 fatty acid. Omega-3 fatty acid causes its prostaglandin-lowering effects through three different mechanisms. First, the much fewer prostaglandins are made from omega-3 fatty acids as compared to the other class of fatty acids in the body, the omega-6 family of fatty acids that originate in the diet from leafy vegetables and other plant sources. Second, the omega-3 fatty acids compete with omega 6 fatty acids for the same binding site on the COX-1 enzyme that converts the omega-6 fatty acids to prostaglandin. The more omega-3 fatty acids present to block the binding sites, the fewer omega 6 fatty acids are able to be converted to prostaglandin. Third, although omega-3 fatty acids also are converted to prostaglandins, the prostaglandins formed from omega-3 are generally 2 to 50 times less active than those formed from the omega-6 fatty acids from dietary plants.  Decrease leukotrine level: Excess production of leukotrienes promotes the inappropriate response to harmless antigenic substances that characterizes allergy. Leukotrienes are fatty acid-derived inflammatory mediators that play a significant role in the pathophysiology of allergic diseases, including asthma, atopic dermatitis, and allergic rhinitis. They are derived from the fatty acid arachidonic acid (AA), which is concentrated in the membrane phospholipids of blood cells. They are synthesized by circulating immune cells in response to a stimulus such as allergen exposure. 72 Maesha Musarrat (Lipids) Diets rich in marine lipids are a good source of omega-3 fatty acid. Eicosapentaenoic acid (EPA), an omega-3 fatty acid, competes with arachidonic acid (AA), an omega-6 fatty acid, for prostaglandin and leukotriene synthesis at the cyclooxygenase and lipoxygenase level. When humans ingest diets rich in marine oil, the omega-3 fatty acids; EPA and docosahexaenoic acid (DHA) from marine oil lead to a decrease in leukotriene B4 formation an inducer of inflammation by inhibiting the action of the 5-lipoxygenase enzyme (5-LO). 73 Maesha Musarrat (Lipids) ❖ Synthetic Lipid: (2013, 2012, 2010) The lipids which are artificially produced in the laboratory are known as synthetic lipids. Comparing with natural lipids, artificial lipids have higher level advantages. These lipids are produced by the combination of sphingolipid and phospholipid. Synthetic lipids are free from bacterial contamination. Recently, high quality fatty acids specially poly unsaturated fatty acids are produced as synthetic lipids. Now, artificial phospholipid having composition of various fatty acids are available adequately.  Examples of synthetic lipid: 1) Lecithin/ Phosphatidyl choline Product name: COTSOME MC – 100 Chemical name: 1,2-didecanoyl-glycero-3-phosphocholine (DDPC) 2) Phosphatidyl glycerol Product name: COATSOME – 21LS Chemical name: Hydrogenated Soyabean Phosphatidyl Glycerol Sodium salt (HSPGS) 74 Maesha Musarrat (Lipids)  Synthetic Phospholipid derivatives: Figure: Phosphotidylcholine Figure: Phosphotidylglycerol Figure: Phosphotidylamine 75 Maesha Musarrat (Lipids) Figure: Phosphotidylacid  Functions of synthetic lipids: 1. Synthetic lipids produced from artificial components are very useful for lung disorder patients. 2. Pulmonary surfactant decreases the surface tension of alveolar wall. In this way protects the lungs from pollution after respiration. Surfactant deficiency results lungs disorder. Generally infants are suffering from this problem. The main components of the surfactant are Dipalmitoyl Phosphatidyl Choline (DPC) and phosphatidyl glycerol. 3. They control delivery of drugs, vitamins and cosmetic materials. 4. They are used in increasing drug formulation in pharmaceuticals companies. 5. Synthetic lipids are used to design new drugs and cosmetics. 76 Maesha Musarrat (Lipids) ❖ The occurrence of main lipids in the human body: (2014) Lipids are an important part of the body, along with proteins, sugars and minerals. Lipids are important for cell membrane structure, regulating metabolism and reproduction, the stress response, brain function and nutrition. Although excess fat in the diet can lead to obesity, lack of lipids in the diet can lead to serious problems, including blood clotting, bone structure and eyesight problems when fat-soluble vitamins are not present in the diet. The occurrence of main lipids in the human body are described below – 1. Cell membranes The cell membrane is comprised of two layers of lipid. The long hydrophobic fatty acid tails of phospholipids and glycolipids clump together in the interior of the membrane and the hydrophilic head groups line the inner and outer sides of the membrane. The membrane separates the inside of the cell from the outside, and most molecules require a specific protein to help it cross the membrane. 2. Hormones Cholesterol is modified into corticosteroids in the adrenal glands. Glucocorticoids regulate the metabolism of sugars and the stress response. Mineralocorticoids regulate the salt and water balance in the body. Cholesterol is also made into androgens, like testosterone, and estrogens, which regulate reproduction and secondary sexual characteristics (that make males look masculine and females look feminine). 3. Fat-soluble vitamins Sunlight helps the body turn cholesterol into Vitamin D, which regulates calcium and phosphorus metabolism and is crucial for strong bones and teeth. Vitamin A is required for retinol production and good eyesight. Vitamin K is required for proper blood clotting. The antioxidant properties of Vitamin E help prevent and repair cell damage. 77 Maesha Musarrat (Lipids) 4. Fat cells Fat cells store concentrated dehydrated triacylglycerols as fat droplets in the cytoplasm. After fasting (when you wake up in the morning) some fat is broken down to fatty acids and released into the blood for use by other cells. Most people have enough fat stored for about a month. 5. Brain Brain cells have long axons and dendrites, and therefore a lot of cell membrane. Sphingomyelin, a phospholipid, forms the myelin sheath that insulates nerve axons, and helps increase the speed of nerve conduction. 6. Blood Cholesterol in the blood is bound to high density and low density lipoproteins (HLD and LDL). Steroid hormones also bind carrier proteins in the blood. Fatty acids released from fat cells into the blood are available to all cells that need energy. ❖ HDL is more important than VLDL: (2009) HDL and VLDL are lipoproteins. Lipoproteins are molecular complexes that consist of lipids and proteins (conjugated proteins). They function as transport vehicles for lipids in blood plasma. Lipoproteins deliver the lipid components (cholesterol, triacylglycerol etc.). There are five major classes of lipoproteins in human plasma. They are chylomicrons, very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). The liver releases VLDL into circulation. VLDL is made up of 55-65% triglycerides, 10-15% cholesterol, 15-20% phospholipid, and 5-10% protein. For comparison, HDL the good holesterol is -50% protein. Once the VLDL is released, enzymes in the bloodstream interact with the triglycerides within the lipoprotein a d ha ge the pa kage fro er lo de sit to lo de sit . LDL is less de se tha VLDL e ause it has lost a large hu k of trigl erides, ha gi g its 78 Maesha Musarrat (Lipids) concentration to 10% triglycerides, 45% cholesterol, 22% phospholipid, and 25% protein. Now, there is an intermediate step between the VLDL and LDL. If LDL level becomes high, an oxidation process takes place that leads to plaque development in artery walls, damage to vessel linings, and heart disease. LDL is also k o as ad holesterol . HDL act in a variety of helpful ways that tend to reduce the risk for heart disease. It scavenges and removes LDL. HDL regulates the movement of cholesterol from tissues to the liver for clearance. The process is called reverse cholesterol transport. If the reverse cholesterol transport process is not functioning efficiently, lipids can build up in tissues such as the arterial wall. Thus, reverse cholesterol transport is essential for avoiding atherosclerosis. HDL reduces, reuses, and recycles LDL cholesterol by transporting it to the liver where it can be reprocessed. They also act as a maintenance crew for the inner walls (endothelium) of blood vessels. Damage to the inner walls is the first step in the process of atherosclerosis, which causes heart attacks and strokes. HDL scrubs the wall clean and keeps it healthy. “o, HDL is k o as good holesterol . Therefore, from the above discussion it can be concluded that HDL is more important than VLDL. 79 Maesha Musarrat (Lipids)