Lipid​ ​metabolism

Source,​ ​function​ ​and​ ​classes​ ​of​ ​lipoproteins

Chylomicrons​ ​(CM)​ ​-​intestine.​ ​Transport​ ​of​ ​dietary​ ​TAG.
Very​ ​low​ ​density​ ​lipoproteins​ ​(VLDL)​ ​-​ ​Liver.​ ​Transport​ ​of​ ​endogenously​ ​synthesized​ ​TAG​ ​to​ ​muscle​ ​and​ ​adipose​ ​tissue
Low​ ​density​ ​lipoproteins​ ​(LDL)​ ​-​Formed​ ​by​ ​circulation​ ​by​ ​partial​ ​breakdown​ ​of​ ​LDL.
​ ​ ​ ​ ​ ​ ​ ​-Delivers​ ​cholesterol​ ​to​ ​peripheral​ ​tissues
High​ ​density​ ​lipoproteins​ ​(HDL)​ ​-​ ​Liver.​ ​Removes​ ​“used”​ ​cholesterol​ ​from​ ​tissues​ ​and​ ​takes​ ​it​ ​to​ ​liver.

Ingested​ ​Lipids
● Rest/Fed​ ​state
● Starving,​ ​Exercise​ ​State
Rest/Fed​ ​state
● storage​ ​:​ ​Lipogenesis
​ ​:​ ​TAG​ ​synthesis/​ ​Esterification
● IMGT​ ​formation
1. F.a.​ ​needs​ ​to​ ​be​ ​activated​ ​by​ ​a​ ​Coenzyme​ ​A
2. Uses​ ​G3P​ ​(glycolysis​ ​intermediate)
3. 3​ ​fattyacyl​ ​CoA​ ​+​ ​G3P​ ​+​ ​H2O​ ​ → ​ ​TAG​ ​+​ ​2CoA​ ​+​ ​Pi
Starving,​ ​Exercise​ ​state
● TAG​ ​breakdown:​ ​Lipolysis​ ​and​ ​B-oxidation
● Lipolysis​ ​:​ ​3​ ​hydrolysis​ ​rxns​ ​which​ ​liberates​ ​3​ ​f.a.​ ​+​ ​glycerol
○ regulated​ ​by​ ​HSL​ ​(hormone​ ​sensitive​ ​lipase)
○ Cytosol
● B-oxidation:​ ​f.a​ ​ → broken​ ​down​ ​to​ ​2​ ​carbons​ ​acetyl​ ​groups​ ​(acetyl​ ​CoA)​ ​ → ​ ​CAC
○ Mitochondrial​ ​matrix
Lipid​ ​metabolism​ ​in​ ​fed​ ​state
1. Dietary​ ​fat​ ​(triglyceride)​ ​is​ ​hydrolyzed​ ​to​ ​ffa​ ​and​ ​glycerol​ ​(actually​ ​monoacylglycerol)​ ​in​ ​the​ ​intestine​ ​by​ ​pancreatic
lipase​ ​(PL)
2. Short​ ​chain​ ​fatty​ ​acids​ ​can​ ​enter​ ​the​ ​circulation​ ​directly,​ ​but​ ​most​ ​fatty​ ​acids​ ​are​ ​re-esterified​ ​with​ ​glycerol​ ​in​ ​the
epithelial​ ​cells​ ​of​ ​the​ ​intestine
● The​ ​resulting​ ​triglycerides​ ​enter​ ​the​ ​circulation​ ​as​ ​lipoprotein​ ​particles​ ​called​ ​chylomicrons​ ​through​ ​the
lymphatic​ ​system
​ ​ ​ ​ ​ ​3.​ ​The​ ​triglycerides​ ​in​ ​chylomicrons​ ​can​ ​be​ ​cleared​ ​by​ ​lipoprotein​ ​lipase​ ​(L)​ ​at​ ​the​ ​endothelial​ ​surface​ ​of​ ​capillaries
● The​ ​resulting​ ​fatty​ ​acids​ ​can​ ​be:
● Stored​ ​as​ ​fat​ ​in​ ​adipose​ ​tissue​ ​(note:triglycerides​ ​(fat)​ ​can​ ​also​ ​be​ ​made​ ​from​ ​excess​ ​glucose​ ​in​ ​the​ ​fed
state);
● Used​ ​for​ ​energy​ ​in​ ​any​ ​tissue​ ​with​ ​mitochondria​ ​with​ ​an​ ​ample​ ​as​ ​their​ ​primary​ ​energy​ ​source​ ​in​ ​the​ ​fed
state.​ ​The​ ​exception​ ​would​ ​be​ ​exercising​ ​muscle);​ ​and
● Re-esterified​ ​to​ ​triglycerides​ ​in​ ​the​ ​liver​ ​and​ ​exported​ ​as​ ​lipoproteins​ ​called​ ​VLDL.​ ​(Note:​ ​Triglycerides
and​ ​VLDL​ ​can​ ​also​ ​be​ ​synthesized​ ​from​ ​excess​ ​glucose​ ​and​ ​amino​ ​acids​ ​in​ ​the​ ​liver​ ​during​ ​fed​ ​state)
● Insulin​ ​stimulates​ ​lipoprotein​ ​lipase.It​ ​also​ ​stimulates​ ​fatty​ ​acid​ ​and​ ​triglyceride​ ​synthesis​ ​in​ ​liver​ ​and
adipose​ ​tissue​ ​and​ ​inhibits​ ​hormone-sensitive​ ​lipase​ ​in​ ​the​ ​adipose​ ​tissue
Lipid​ ​metabolism​ ​during​ ​fasting​ ​&​ ​exercise
1. Glycogen​ ​breakdown​ ​provides​ ​glucose,​ ​protein​ ​breakdown​ ​provides​ ​alanine,​ ​which​ ​is​ ​converted​ ​to​ ​glucose​ ​in​ ​the
liver​ ​(gluconeogenesis)
● The​ ​blood​ ​glucose​ ​is​ ​used​ ​by​ ​the​ ​brain​ ​and​ ​red​ ​blood​ ​cells.​ ​Most​ ​other​ ​tissues,​ ​including​ ​resting​ ​muscle​ ​,
rely​ ​primarily​ ​on​ ​fatty​ ​acids​ ​as​ ​an​ ​energy​ ​source
● Exercising​ ​muscle​ ​will​ ​use​ ​both​ ​fatty​ ​acids​ ​and​ ​glucose​ ​for​ ​energy
● The​ ​relative​ ​contribution​ ​these​ ​energy​ ​sources​ ​depends​ ​on​ ​the​ ​intensity​ ​of​ ​the​ ​exercise
​ ​ ​ ​ ​ ​2.​ ​hormone​ ​-sensitive​ ​lipase​ ​is​ ​activated​ ​by​ ​glucagon​ ​(fasting)​ ​or​ ​epinephrine​ ​(exercise).​ ​Therefore,​ ​fat​ ​in​ ​adipose
tissue​ ​is​ ​hydrolyzed​ ​to​ ​give​ ​glycerol​ ​and​ ​fatty​ ​acids​ ​during​ ​both​ ​fasting​ ​and​ ​exercise
​ ​ ​ ​ ​ ​3.​ ​The​ ​fatty​ ​acids​ ​can​ ​be​ ​used​ ​directly​ ​as​ ​an​ ​energy​ ​source​ ​by​ ​most​ ​tissues​ ​with​ ​mitochondria.
The​ ​glycerol​ ​can​ ​be​ ​converted​ ​to​ ​glucose​ ​in​ ​the​ ​liver.​ ​This​ ​is​ ​a​ ​minor​ ​source​ ​of​ ​glucose​ ​-​ ​ ​gluconeogenesis
​ ​ ​ ​ ​5.​ ​Glucagon​ ​&​ ​epinephrine​ ​stimulate​ ​hormone-sensitive​ ​lipase​ ​and​ ​inhibit​ ​lipoprotein​ ​lipase,​ ​fatty​ ​acid​ ​synthesis​ ​and
triglyceride​ ​synthesis
​ ​ ​ ​ ​6.​ ​DUring​ ​prolonged​ ​starvation,​ ​the​ ​fatty​ ​acids​ ​can​ ​also​ ​be​ ​converted​ ​to​ ​ketone​ ​bodies​ ​in​ ​the​ ​liver.
Ketone​ ​bodies​ ​can​ ​be​ ​used​ ​as​ ​an​ ​energy​ ​source​ ​by​ ​all​ ​tissue​ ​except​ ​those​ ​lacking​ ​mitochondria​ ​(e.g.​ ​red​ ​blood
cells)
Brain​ ​adapts​ ​slowly​ ​to​ ​the​ ​use​ ​of​ ​ketone​ ​bodies​ ​during​ ​prolonged​ ​starvation.
 Synthesis​ ​of​ ​triglycerides​ ​is​ ​anabolic​ ​therefore​ ​needs​ ​inhibitor(?).​ ​Fatty
acylCoA​ ​needs​ ​3​ ​of​ ​that​ ​to​ ​be​ ​attached​ ​to​ ​a​ ​glycerol​ ​coming​ ​from​ ​G3P
of​ ​glycolysis.​ ​When​ ​glycerol​ ​from​ ​glycolysis​ ​attaches​ ​or​ ​fattyacylCoA
attaches​ ​to​ ​glycerol​ ​is​ ​called​ ​esterification.​ ​3​ ​of​ ​the​ ​fattyacylCoA
attached​ ​to​ ​the​ ​glycerol​ ​if​ ​you​ ​have​ ​the​ ​tricylglyceride.
Glycerol​ ​and​ ​Fatty​ ​acids​ ​via​ ​hormone​ ​sensitive​ ​lipase​ ​interacting
*inaudible*​ ​What​ ​happens​ ​to​ ​the​ ​glycerol?​ ​It​ ​comes​ ​out​ ​and​ ​becomes
blood​ ​glycerol​ ​and​ ​fatty​ ​acids​ ​becomes​ ​bloodfree​ ​ffa​ ​and​ ​it​ ​trasnports​ ​to
whatever​ ​it​ ​is​ ​needed​ ​for​ ​breakdown

Key​ ​points​ ​of​ ​control​ ​of​ ​fatty​ ​acid​ ​metabolism​ ​during​ ​fasting,​ ​starvation​ ​and​ ​exercise
● Glucagon​ ​activates​ ​hormone​ ​sensitive​ ​lipase​ ​(HSL).​ ​Fatty​ ​acids​ ​are​ ​released​ ​from​ ​adipose​ ​tissue
● Mass​ ​action​ ​drives​ ​B-oxidation​ ​in​ ​the​ ​liver.​ ​Acetyl-CoA​ ​is​ ​produced
● Glucagon​ ​inhibits​ ​fatty​ ​acid​ ​and​ ​triglyceride​ ​synthesis
● Most​ ​of​ ​the​ ​acetyl-CoA​ ​enters​ ​the​ ​C.A.C​ ​and​ ​is​ ​used​ ​for​ ​energy​ ​production
● As​ ​glycogen​ ​stores​ ​are​ ​depleted​ ​and​ ​gluconeogenesis​ ​depletes​ ​OAA​ ​levels,​ ​acetyl-CoA​ ​cannot​ ​be​ ​used​ ​by​ ​the
mitochondria​ ​and​ ​ketone​ ​body​ ​production​ ​becomes​ ​more​ ​prominent
Fatty​ ​acids
● Simple​ ​fats/lipids
● 4-24​ ​carbon​ ​atoms​ ​+​ ​carboxyl​ ​grp
● Saturated​ ​and​ ​unsaturated
● Essential​ ​fatty​ ​acids
● Linoleic​ ​acid-precursor​ ​of​ ​other​ ​fatty​ ​acids;​ ​integrity​ ​of​ ​plasma​ ​membrane,​ ​growth,​ ​reproduction​ ​and​ ​skin
maintenance
● *remember​ ​the​ ​structure*
Regulation​ ​of​ ​TAG​ ​turnover
● Formation​ ​and​ ​degradation​ ​->​ ​cytosol
● Regulation​ ​is​ ​through​ ​the​ ​activation​ ​(phosphorylation)
● hormones:
-glucocorticoids​ ​(cortisol):
● ↑ hydrolysis
-insulin:
● ↑ ​ ​synthesis
-catecholamines:
● B-receptors​ ​-​ ​ ↑ lipolysis
● Alpha-receptors​ ​-​ ​ ↑ ​ ​synthesis

Formation​ ​of​ ​ketone​ ​bodies

Starvation,​ ​fasting,​ ​extreme​ ​exercise)
● Low​ ​CHO​ ​for​ ​energy
● ↑ ​ ​fatty​ ​acid​ ​entry​ ​into​ ​the​ ​liver​ ​mitochondria
● ↑ B-oxidation​ ​of​ ​fatty​ ​acyl-CoA
● ↑ acetyl-CoA​ ​formation​ ​w/c​ ​exceeds​ ​the​ ​capacity​ ​of​ ​the​ ​liver​ ​mitochondria​ ​to​ ​oxidize​ ​by​ ​CAC
● Excess​ ​acetyl-CoA​ ​forms​ ​acetoacetate
● Excess​ ​acetoacetate​ ​reduced​ ​to​ ​3​ ​hydroxybutyrate
The​ ​Metabolic​ ​Mill
The​ ​use​ ​of​ ​other​ ​fuels​ ​such​ ​as​ ​fatty​ ​acids​ ​and​ ​amino​ ​acids​ ​is​ ​largely​ ​determined​ ​by​ ​the​ ​availability​ ​of
acetyl-CoA(monocarboxylates)​ ​from​ ​glycolysis
“Fats​ ​burn​ ​in​ ​carbohydrate​ ​flame”​ ​-​explain​ ​this​ ​in​ ​the​ ​exam
● Fro​ ​full​ ​oxidation​ ​of​ ​fatty​ ​acids,​ ​acetyl-CoA​ ​from​ ​B-oxidation​ ​goes​ ​through​ ​CAC
● For​ ​CAC​ ​to​ ​continue,​ ​oxaloacetate​ ​needs​ ​to​ ​be​ ​regenerated​ ​through​ ​the​ ​entry​ ​of​ ​substrates​ ​from​ ​glucose
metabolism
● Since​ ​low​ ​CHO,​ ​low​ ​oxaloacetate​ ​regeneration
 ● CAC​ ​slows​ ​down
● Full​ ​oxidation​ ​of​ ​fatty​ ​acid​ ​for​ ​ATP​ ​synthesis​ ​slows​ ​down​ ​which​ ​accumulates​ ​acetyl-CoA
● Accumulated​ ​acetyl-CoA​ ​forms​ ​ketones
What​ ​happens​ ​to​ ​the​ ​ketone​ ​bodies?
● Temporary​ ​fuel​ ​for​ ​skeletal​ ​muscle,​ ​heart​ ​and​ ​brain
● Ketoacidosis​ ​-​ ​formation​ ​of​ ​ketones​ ​liberates​ ​H+​ ​which​ ​decreases​ ​pH
-excreted​ ​in​ ​the​ ​urine​ ​-​ ​Ketonuria
-Ketonemia
-acetone​ ​breath
-elevated​ ​blood​ ​ffa​ ​concentration
-hypoglycemia
-hyperglycemia​ ​for​ ​diabetic​ ​persons
Overall​ ​schema​ ​for​ ​synthesis​ ​of​ ​triglycerides​ ​from​ ​glucose​ ​*study​ ​the​ ​picture*

-grand​ ​mixture​ ​of​ ​amino​ ​acids​ ​available​ ​in​ ​the​ ​cell​ ​derived​ ​from​ ​dietary
sources​ ​or​ ​the​ ​degradation​ ​of​ ​protein
More​ ​on:​ ​http://chemistry.elmhurst.edu/vchembook/630proteinmet.html

Transcription​ ​and​ ​translation

● Cells​ ​are​ ​governed​ ​by​ ​a​ ​cellular​ ​chain​ ​of​ ​command
-DNA​ ​ → RNA​ ​ → protein
● Transcription
-is​ ​the​ ​synthesis​ ​of​ ​RNA​ ​under​ ​the​ ​direction​ ​of​ ​DNA
-produces​ ​messenger​ ​RNA​ ​(mRNA)
● Translation
-is​ ​the​ ​actual​ ​synthesis​ ​of​ ​a​ ​polypeptide,​ ​which​ ​occurs​ ​under​ ​the​ ​direction​ ​of​ ​mRNA
-occurs​ ​on​ ​ribosome
Genetic​ ​code​ ​and​ ​translation
Translation​ ​-​synthesis​ ​of​ ​a​ ​protein​ ​at​ ​the​ ​ribosome​ ​in​ ​response​ ​to​ ​the​ ​codon​ ​of​ ​mRNA
​ ​ ​ ​ ​ ​ ​-​ ​mRNA​ ​+​ ​tRNA​ ​(anticodon​ ​+​ ​a.a)​ ​+​ ​ribosome
3​ ​nucleotide​ ​sets:
“Codon”​ ​(on​ ​the​ ​mRNA)
“Anticodon”​ ​(on​ ​the​ ​tRNA)​ ​+​ ​specific​ ​amino​ ​acid
We​ ​can​ ​divide​ ​translation​ ​into​ ​3​ ​stages
-initiation
-elongation
-termination
Hormones​ ​that​ ​promote​ ​synthesis
● Insulin
● IGG​ ​(insulin​ ​growth​ ​factor)
● Growth​ ​hormone
● Testosterone
​ ​Dietary​ ​protein​ ​degradation
● Dietary​ ​proteins​ ​are​ ​hydrolyzed​ ​to​ ​amino​ ​acids​ ​and​ ​absorbed​ ​into​ ​the​ ​bloodstream
Proteins​ ​-​ ​a​ ​polymer​ ​of​ ​amino​ ​acids
Peptide​ ​bond​ ​-formed​ ​by​ ​dehydration​ ​synthesis
- Amine​ ​group​ ​of​ ​one​ ​amino​ ​acid​ ​binds​ ​with​ ​carboxyl​ ​group​ ​of​ ​another​ ​amino​ ​acid
Degradation​ ​of​ ​proteins
Poteinases​ ​(peptidase/proteases)-​ ​protein​ ​degrading​ ​enzyme
Skeletal​ ​muscle​ ​systems​ ​of​ ​degradation​ ​(cytosolic​ ​peptidases):
1. Ubiquitin-proteasome​ ​pathway
Marking​ ​(label)​ ​proteins​ ​for​ ​degradation​ ​with​ ​subsequent​ ​breakdown​ ​to​ ​small​ ​peptides​ ​by​ ​a​ ​proteasome​ ​complex
​ ​ ​ ​ ​ ​ ​2.​ ​Lysosomal​ ​system
 Internal​ ​cell​ ​organelles​ ​with​ ​proteinases​ ​called​ ​cathepsins​ ​which​ ​degrade​ ​by​ ​cleaving​ ​amino​ ​acids​ ​one​ ​at​ ​a​ ​time
from​ ​both​ ​amino​ ​and​ ​carboxyl​ ​ends
​ ​ ​ ​ ​ ​ ​3.​ ​Calpain​ ​system
A​ ​family​ ​of​ ​calcium​ ​activated​ ​proteases​ ​found​ ​in​ ​the​ ​cytosol
Calpain​ ​system
● Involved​ ​in​ ​the​ ​initial​ ​fragmentation​ ​of​ ​structural​ ​proteins,​ ​contractile​ ​proteins​ ​and​ ​membrane​ ​proteins
● With​ ​severe​ ​exercise​ ​and​ ​eccentric​ ​muscle​ ​action,​ ​calpain​ ​activation/activity​ ​is​ ​increased​ ​due​ ​to​ ​disturbance​ ​in
calcium​ ​regulation/prolonged​ ​high​ ​calcium​ ​concentration​ ​in​ ​the​ ​cytosol
General​ ​processes​ ​of​ ​breakdown
● Polypeptide​ ​breakdown
● Amino​ ​acid​ ​breakdown
● Nitrogen​ ​disposal​ ​(urea​ ​formation)
● Carbon​ ​skeleton​ ​fates​ ​(energy​ ​systems)
Protein​ ​metabolism​ ​in​ ​the​ ​liver
● Responsible​ ​for​ ​much​ ​of​ ​aa​ ​metabolism
● Takes​ ​up​ ​as​ ​much​ ​as​ ​50%​ ​of​ ​dietary​ ​aa
● Regulates​ ​composition​ ​of​ ​aa​ ​pool
● Synthesizes​ ​almost​ ​all​ ​aa