Regulation of FAS and Cholesterol Metabolism Flashcards Preview

DM Biochem > Regulation of FAS and Cholesterol Metabolism > Flashcards

Flashcards in Regulation of FAS and Cholesterol Metabolism Deck (15)
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1

which enzyme is common to both fatty acid synthesis and cholesterol synthesis?

citrate lyase is needed in the cytosol to create acetyl CoA

2

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

3

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

4

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

5

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 

6

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

7

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

8

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

9

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

10

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)

11

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

12

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

13

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

14

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

15

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