Lipid Metabolism: Hirowati Ali

Lipid Metabolism
Hirowati Ali
Overview
• Most of the lipids in our body are categorized as :
– Fatty acids which were stored as triacylglycerols
– Glycerophospholipids and sphingolipids (contain esterified
fatty acids found in membranes and in blood lipoproteins)
– Eicosanoids (consists of polyunsaturated fatty acids contai
ning 20 carbons which regulate many cellular processes)
– Cholesterol (adds stability to the phospholipid bilayer of m
embranes and serves as the precursor of bile salts, deterge
nt like compounds that function in the process of lipid dige
stion and absorption; steroid hormones which act for the r
egulation of metabolism, growth, and reproduction).
– Bile salts
– Steroid hormones
– Fat-soluble vitamins (lipids that are involved in var
ied function as vision, growth, and differentiation (
vitamin A), blood clotting (vitamin K), prevention o
f oxidative damage (vitamin E), and calcium metab
olism (vitamin D)
• Numerous functions of lipid :
– Thermal insulation
– Energy storage (triacylglycerol)
– Metabolic fuels
– Membrane components (phospholipids and chole
sterol)
– Hormones (steroids and vitamin D metabolites)
– Precursors of prostaniods and leukotrienes
– Emulsifying agents in the digestion and absorption
of lipids (bile acids)
– Surfactant in alveolar membrane (phosphatidylch
oline)
• Fatty acids contain no carbon-carbon double b
onds - saturated fatty acid
• Fatty acids contain carbon-carbon double bon
ds  unsaturated fatty acid
• Most abundant saturated fatty acids : palmitic
and stearic acids
Oxidation of fatty acids
• Overall process : mitochondria
• Acyl-Co-A synthase : the major activating enzyme; occurs
on the outer mitochondrial membrane surface and in end
oplasmic reticulum.
• At least, 3 acyl Co-A synthases :
– Acetyl Co-A acts on acetate and other low-molecular-w
eight carboxylic acids
– Medium chain acyl Co-A synthase (with 4-11 carbon at
oms
– Acyl Co-A synthase on fatty acids with 6 – 20 carbon at
oms
• Acetyl Co-A synthase in muscle is restricted to
the mitochondrial matrix
• Medium chain acyl Co-A synthase occurs only i
n liver mitochondria where medium chain fatt
y acids obtained from digestion of dietary tricy
lglycerols and transported by the portal blood
are metabolized
Carnitine
• In human, carnitine production : liver and kidney, the
n transported to skeletal and cardiac muscle, where i
t can not be synthesized
• Transport of acyl Co-A to mitochondrial matrix is acc
omplished by CARNITINE (L-β-hydroxy-γ-trimethylam
monium butyrate) which is required in catalytic amo
unts for the oxidation of fatty acids.
• Carnitine also participates in the transport of acetyl C
o-A for cytosolic fatty acids synthesis.
• There are 2 types of carnitine acyl transferase
for Acyl Co-A transport:
– Carnitine palmitoyltransferase I (CPT I) : located o
n outer surface of inner mithochondria membrane
– Carnitine palmitoyltransferase II (CPT II) : located o
n inner surface
β-oxidation
• As major pathway for fatty acid oxidation
Sudden infant
death syndro
me
HELLP (hemolysis,elevate
d liver enzyme levels and l
ow platelet countt) Syndro
me
Other pathways of fatty acid oxidation
• Peroxisomal oxidation  abundant in liver and ki
dney. Acyl CoA derivatives transported across the
membran without involvement of carnitine. Pero
xisomal oxidation does not yield ATP but appears
as heat.
• Propionyl-CoA oxidation. Propionyl CoA is small in
diet and yields from catabolism of isoleucine, vali
ne, methionine, and threonine.
• α-oxidation, is important in the catabolism of bra
nched chain fatty acids.
Long-chain saturated fatty acids
• Synthesis takes place in the cytosol (whereas f
atty acid oxidation occurs in mitochondria)
• All carbon atoms are derived from acetyl-CoA
(obtained from carbohydrate and amino acid)
and palmitate (C16)
• The comitted step is the biotin-dependent enz
yme carboxylation of acetyl-CoA by acetyl-CoA
carboxylase
Fatty acid synthesis
• Fatty acids are synthesized whenever an excess of
calories is ingested.
• The major source for fatty acid synthesis is dietar
y carbohydrate.
• An excess of dietary protein can also result in an i
ncreased fatty acid synthesis.
• When an excess of dietary carbohydrate is consu
med, glucose is converted to acetyl Co-A which pr
ovides 2 carbon units that in condense in a series
of reaction on the fatty acids synthase complex, l
ocated in cytosol.
• From acetyl Co-A, an enzyme acetyl CoA carbo
xylase produces Malonyl Co-A
• The growing fatty acid chain, attached to fatty
acid synthase complex, it produces palmitate.
• After activation to a Co-A derivative, palmitate
can be elongated and desaturated to produce
a series of fatty acids.
• Fatty acids produced in cells or obtained from
diet, are used by various tissues for the synthe
sis of triacylglycerols, glycerophospholipids an
d sphingolipids (the major components of cell
membranes).
• Triacylglycerol, the major dietary lipids, are digest
ed in the lumen of intestine
• The initial digestive products, free fatty acid and 2
-monoacyl glycerol, are reconverted into triacylgl
yecrols in intestine epithelial cells, packaged in lip
oproteins known as chylomicrons, so can safely e
nter the circulation,and secreted into the lymph,
enter the blood, serving as one of the major lipop
roteins.
• Very low density lipoprotein (VLDL), is produc
ed in the liver, mainly from dietary carbohydra
te.
• Lipogenesis : an insulin stimulated process thr
ough which glucose is converted to fatty acids,
esterified to glycerol to form triacylglycerol th
at are packaged in VLDL and secreted from the
liver.
• Thus, chylomicrons primarily transport dietary lipids, a
nd VLDL transport endogenously synthesized lipids.
• Triacylglycerols of chylomicrons and VLDL are digested

by lipoprotein lipase (LPL), an enzyme attahced to capil
lary endothelial cells.
• LPL converts chylomicrons into chylomicron remnant a

nd VLDL to intermediate density lipoprotein (IDL). Thes
e products rae low triacylglycerol content, are taken up
by the liver by the process endocytosis and degraded b
y lysosomal action. IDL may also converted into Low de
nsity lipoprotein (LDL). Endocytosis of LDL occurs in per
ipheral tissues and liver, and major means of cholester
ol transport and delivery to peripheral tissues.
• Fatty acids that are released are taken up by m
uscle and other tissues and oxidized to CO2 an
d water to produce energy.
• After a meal, these fatty acids are taken up by
adipose tissue and stored as triacylglycerols.
Digestion of triacylglycerols
• Triacylglycerols are the major fat in human die
t.
• Triacylglycerols contain glycerol and three fatt
y acids.
• Main route of triacylgliserol digestion : hydroly
sis to fatty acids by lingual and gastric lipases;
and 2-monoacylglycerol in lumen intestine.
• Leaving the stomach, fat enters the small intes
tine, where it is suspended into small particles
in the aqueous environment by bile salts whic
h is containing both hydrophobic and hydrophi
lic components, synthesized in the liver and se
creted via gallbladder into intestinal lumen wit
h involvement of cholecystokinin (gut hormon
e) which is secreted by the intestinal cells whe
n stomach contents enter the intestine.
• Pancreatic lipase and colipase, are secreted in
response to the release of cholesystokinin fro
m the intestine.
• The peptide hormone, secretin, is also release
d by small intestine in response to acidic mate
rials (such as partially digested materials from
stomach, which contains HCl) entering the du
odenum.
• Secretin, signals the liver, pancreas, and certai
n intestinal cells to secrete bicarbonate which
raises the pH into range pH 6, that is optimal f
or the action of all digestive enzymes of the in
testine.
• Bile salts inhibit pancreatic lipase activity by c
oating the substrate and not allowing the enzy
me access to the substrate.
• The colipase, binds to dieatry fat and to lipase,
by relieving bile salt inhibition, and allowing tr
iglyceride to enter active site of the lipase and
enhances lipase activity.
• Pancreatic lipase hydrolyzes triacilglycerol, pro
ducing three fatty acids and 2-monoacylglycer
ol
• Dietary phospholipids are hydrolized by pancr
eatic phospholipase A2 in intestine
• Dietary cholesterols esterified to fatty acids ar

e hydrolized by pancreatic cholesterol esterase
in intestine
Absorption of dietary lipids
• Fatty acids and 2-monoacylglycerols produced by
digestion, are packaged into micelles (tiny microd
roplets that emulsified by bile salts).
• Other dietary lipids, such as cholesterol, lysophos
pholipids, and fat soluble vitamins, are also packa
ged in these micelles.
• Micelles travel through a layer of water to the mic
rovilli on the surface of intestinal epithelial cells, t
hose dietary lipids are absorbed, but bile salts are
left behind in the lumen of the gut.
• The bile salts are resorbed when they reach ileum
. More than 95% of the bile salts are recirculated,
traveling through enterohepatic circulation to the
liver, which secretes them into the bile for storag
e in the gallbladder and ejection into intestinal lu
men during another digestive cycle.
• Short and medium chain fatty acids (C4 to C12) d
o not require bile salts. They directly absorbed int
o intestinal epithelial cells, because they do not n
eed to be packaged to increase their solubility, th
ey enter the portal blood and are transported to t
he liver bound to serum albumin.
Synthesis of chylomicrons
• In the intestinal epithelial cells, fatty acids and 2-m
onoacylglyserols are condensed by enzymatic react
ion in the smooth endoplasmic reticulum to form t
riacylglycerols.
• Triacylglycerols are transported in lipoprotein parti
cles because they are insoluble in water. If triacylgl
ycerols entered the blood directly, they would coal
esce, impeding blood flow. Intestinal cells package
triacylglycerols together with proteins and phosph
olipids in chylomicrons.
• Chylomicrons also contain cholesterol and fat-sol
uble vitamins, but their major component is trigly
ceride derived from diet. The protein constituents
of the lipoprotein are known as apoproteins.
• The major apoprotein associated with chylomicro
ns as they leave intestinal cells is B-48. The B-48 a
poprotein is structurally and genectically related t
o the B-100 apoprotein synthesized in the liver an
d serves as a major protein of VLDL.
Transport of lipids in the blood
• By exocytosis,nascent chylomicrons are secret
ed by the intestinal epithelial cells into the chy
le of lymphatic system and enter the blood th
orugh thoracis duct. Nascent chylomicrons be
gin to enter the blood within 1 to 2 hours after
the start of a meal. As the meal is digested an
d absorbed, they continue to enter the blood f
or many hours.
• As they accept proteins from high density lipopro
tein (HDL) within the lymph and the blood, they b
ecome mature chylomicrons.
• HDL transfers proteins to the nascent chylomicro
ns, particularly, ApoE and ApoCII. ApoE is recogni
zed by membrane receptors, mostly those on the
surface of the liver cells, allowing ApoE bearing li
poproteins to enter the cells by endocytosis for s
ubsequent digestion by lysosomes.
• ApoCII acts as an activator of LPL, the enzyme
on capillary endothelial cells, primarily within
muscle and adipose tissue, which digest the tri
acylglycerols of chylomicrons and VLDL in the
blood.
Cholesterol
• Cholesterol is transported in the blood in lipoprot
eins because of its absolute insoluble in water.
• Cholesterol, serves as a stabilizing component of
cell membranes and as a precursor of bile salts an
d steroid hormones.
• Cholesterol is obtained from diet or synthesized b
y a pathway that occurs in most cells of the body,
but to greater extent in cells of liver and intestine.
• The precursor for cholesterol synthesis is acety
l coenzyme A (acetyl CoA), which can be produ
ced from glucose, fatty acids, or amino acids.
• Two molecules of acetyl Co-A form acetoacety
l CoA, which condenses with other acetyl CoA
to form hydroxymethylglutaryl-CoA (HMG CoA
).
• Reduction HMG CoA produces Mevalonate by H
MG CoA reductase.
• Mevalonate produces isoprene units and forming
squalene. Cyclization of squalene produces the st
eroid ring system and several subsequent reactio
ns generate cholesterol.
• The adrenal cortex and the gonads also synthesiz
ed cholesterol in significant amounts and use it as
a precursor for steroid hormone synthesis.
• Cholesterols are packaged in chylomicrons in t
he intestine and in VLDL in the liver.
• It is transported in the blood in these lipoprot
ein particles,which also transport triacylglycer
ols.
• Tricylglycerols of blood lipoprotein are digeste
d by lipoprotein lipase chylomicrons are con
verted to chylomicron remnants, and VLDL is c
onverted into IDL and VLDL.
• Reference : Mark’s Basic Medical Biochemistry

Lipid Metabolism: Hirowati Ali

Uploaded by

Copyright:

Available Formats

Lipid Metabolism: Hirowati Ali

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Lipid Metabolism: Hirowati Ali

Uploaded by

Copyright:

Available Formats

Lipid Metabolism

• Triacylglycerols of chylomicrons and VLDL are digested

• LPL converts chylomicrons into chylomicron remnant a

• Dietary cholesterols esterified to fatty acids ar

You might also like