Regulation of FAS and Cholesterol Metabolism Flashcards
which enzyme is common to both fatty acid synthesis and cholesterol synthesis?
citrate lyase is needed in the cytosol to create acetyl CoA
how is acetyl CoA carboxylase regulated?
- substrate availability: cytosolic acetyl CoA
- allosteric: activated by citrate and inhibited by palmitoyl CoA
- covalent: activated by dephosphorylation and inhibited by phosphorylation
- polymer is active and protomer is inactive
- enzyme induction by insulin
describe the polymer vs protomer form of acetyl CoA carboxylase
- citrate shifts the equilibrium towards polymer formation using protomers – activation
- palmitoyl CoA shifts the equilibrium towards protomer formation (depolymerization) – inhibition
what causes feed-forward activation of acetyl CoA carboxylase?
- citrate is found in cytosol when mt citrate levels are very high
- at this time, citrate has to be used for de-novo synthesis of fatty acid (or cholesterol synthesis)
- once in the cytosol, citrate up regulates ACC and leads to polymer formation
what causes feedback inhibition of acetly CoA carboxylase
- feedback inhibition is caused by palmityl acyl CoA
- free palmitates have detergent character
- an accumulation of long-chain fatty acyl CoA indicates that synthesis of TAGs is slow and that the pool of free CoA is getting low
- fatty acid synthesis is slowed down so that less palmitates are formed
how is acetyl CoA carboxylase regulated by covalent modification?
- ACC is active when dephosphorylated and inactive by phosphorylation
- insulin favor de-novo synthesis of FAs and therefore leads to the active dephosphorylated form of ACC
- insulin also induces gene expression of ACC
explain how ACC activity is regulated by the energy status of the hepatocytes and by hormones (blood glucose levels)
- ACC is inhibited when it is phosphorylated by AMPK
- actviation of AMPK:
- allosteric by AMP
- covalent by phosphorylation that is caused by glucagon, epinephrine, norepi
describe how diets affect long-term regulation of ACC in de novo synthesis of FAs
- high carbohydrate and fat-free diets and insulin lead to increased synthesis of ACC (up regulation and induction) resulting in increased synthesis of FA
- high fat diets, fasting and glucagon lead to decreased synthesis of ACC resulting in decreased synthesis of Fa
describe malonyl CoA’s inhibition of carnitine-palmitoyl transferase (CPT 1)
-
malonyl-CoA formed in cytosol during FA synthesis inhibits CPT I which is involved in the transport of long-chain FAs into the mt for B-oxidation
- this ensures that during FA synthesis, B-oxidation is inhibited
- newly synthesized FA remain in the cytosol and are not immediately oxidized in the fed state
describe the principal regulated enzyme in cholesterol synthesis
HMG CoA reductase
- phosphorylation by cAMP-dependent kinases inactivates the reductase
- HMG CoA reductase is activated by substrate availability (HMG CoA in cytosol)
how does cytosolic cholesterol affect gene expression of HMG CoA reductase
- high cytosolic cholesterol levels leads to:
- inhibition of transcription of HMG CoA reductase
- down regulation of cholesterol synthesis
- early degradation of available enzyme
describe sterol-acclerated enzyme degradation
- degradation of HMG CoA reductase is also controlled by the ubiquitin system in protesomes
- high intracellular concentrations of derivatives of cholesterol (like lanosterol) and/or mevalonate leads to rapid degradation (proteolysis) of the HMG CoA reductase by the ubiquitin system in protesomes
describe sterol independent phosphorylation/dephosphorylation
- high intracellular concentrations of AMP (low cellular energy) stimulate AMPK
- AMPK phosphorylates/inactivates HMG CoA reductase
- dephosphorylation by a phosphoprotein phosphatase (activated by insulin) activates HMG CoA reductase
contrast short term vs long term affects of insulin on HMG CoA reductase
- short term: insulin leads to dephosphorylated HMG CoA reductase (active)
- long term: insulin favors upregulation of the expression of the gene for HMG CoA reductase
describe the effects of statin drugs
- statin drugs are structural of HMG CoA and act as reversible competitive inhibitors of HMG CoA reductase
- prevents synthesis of cholesterol
- hepatocytes will have decreased cytosolic cholesterol so the liver will increase LDL receptors which will cause a decrease in serum LDL and serum cholesterol
