Biochem - Unit II - cholesterol

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  1. To compare and contrast the different mechanisms by which cholesterol biosynthesis are regulated.
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  2. To predict whether intracellular cholesterol synthesis will be up- or down-regulated in response to energy availability as influenced by diet, hormones and exercise.
    s
  3. To distinguish the different mechanisms by which plasma cholesterol levels are controlled by clinically adminstrered pharmacological agents.
    s
  4. Cholesterol distribution gradient
    nuclear envelope/RER < SER < Golgi < Plasma membrane
  5. five major hormones derived from cholesterol
    • C21: progestagens, glucocorticoids, mineralcorticoids
    • C19: androgen
    • C18: estrogen
  6. synthesis of cholesterol
    • A. acetyl CoA ->-> HMG CoA; enzyme of the final step - HMG CoA synthase
    • B. HMG CoA -> mevalonic acid; Enzyme - HMG CoA reductase; rate limiting step
    • C. mevalonic acid ->...-> cholesterol, energy consuming, only happens w/ excessive energy
  7. The transcription factor regulating cholesterol synthesis genes is ______.
    SREBP - sterol responsive element binding protein
  8. Cholesterol dependent regulation when level is low
    • SREBP: SCAP binding area; DNA binding area
    • SCAP: cholesterol sensing sequence
    • SREBP-SCAP senses low cholesterol in ER -> leave and move to Golgi
    • At Golgi, protease 1 and 2 cleave SREBP off
    • SREBP is translocated to nucleus, binds to SRE (sterol regulating element), starts transcribing the SRE controlled genes.
  9. Cholesterol dependent regulation on HMG CoA
    • HMC CoA reductase (HMGR) correctly folded and stable when cholesterol is low
    • becomes misfolded and gets degraded when cholesterol is high, inhibiting the transformation from HMG CoA to mevalonic acid, which is the rate limit step in cholesterol synthesis; irreversible
  10. Cholesterol dependent regulation on HMG CoA phosphorylation
    • ATP↓ -> AMP↑ -> AMP kinase (not PKA)↑ 
    • AMP kinase -> HMGR phosphorylation -> cholesterol synthesis inhibited
    • reversible
  11. Hormonal regulation on HMGR expression and activity
    • insulin stims
    • glucagon inhibits
  12. Statins mechanisms
    mimic transient intermediate mevadyl CoA

    competitively inhibit HMGR
  13. Zetia (ezetimibe)
    • • acts at small intestine brush border
    • • does not enter the bloodstream, no side effects
    • • inhibits absorption of cholesterol
    • • does not block absorption of triglycerides or
    • fat-soluble vitamins
  14. _________is the principal mechanism for eliminating cholesterol from the body
    Excretion of bile salts
  15. ezetimibe + simvastatin
    • • further reduces total cholesterol levels as compared to statin alone
    • • blocks intestinal cholesterol absorption and synthesis in liver
    • • permits reduced doses of statins to minimize the side effects
  16. Bile acids and bile salts
    • • cholesterol is the precursor of bile acids and bile salts
    • • synthesized in the liver
    • • stored in the gall bladder
    • • secreted into intestine
    • • aid digestion by emulsifying dietary lipids making them accessible to pancreatic lipases
    • • aid intestinal absorption of fat-soluble vitamins (A, D, E, K)
    • • ~95% are reabsorbed in ileum and returned to liver
    • • ~5% of bile salts are excreted in feces
  17. Enterohepatic circulation of bile acids and salts
    • • synthesis in the liver
    • • storage in the gall bladder
    • • secretion into intestine
    • • recirculation to liver
  18. Primary bile acids
    - composition
    - rate limiting step enzyme
    - regulator
    • - cholic acid, chenodeoxycholic acid
    • - 7-α-hydroxylase
    • - cholic acid inhibits; cholesterol stims
  19. secondary cholic acids
    • deoxycholic acid
    • lithocholic acid
  20. Hypercholesterolemia is often treated with
    • compounds that sequester bile acids in the intestine.
    • Sequestrants:
    • prevent reabsorbtion of bile acids
    • increase conversion of cholesterol to bile acids
    • increase bile salt elimination in feces
    • Dietary fiber also sequesters bile acids
  21. lipoprotein particles anatomy
    • outer: apoprotein + single layer phospholipid + cholesterol
    • inner: cholesterol-ester and triglyceride
  22. Lipoprotein particles - general characteristics and functions
    • • spherical particles with varying amounts of lipid and protein
    • • maintain solubility of constituent lipids
    • • transport of lipids in plasma
  23. Major classes of lipoprotein particles
    • • chylomicrons; has the highest percentage of triglycerides
    • • VLDLs - very low density lipoproteins
    • • LDLs - low density lipoproteins; highest percentage of cholesterol
    • • HDLs - high density lipoproteins; highest percentage of protein; removes cholesterol from blood
  24. apolipoproteins
    • - five classes A-E
    • - important in release of lipoprotein particles from cell
    • - activate lipid-processing enzymes in blood
    • - mediate uptake of lipoprotein particles into cells
  25. Cholesterol is absorbed in the ______ and assembled into ______.
    • small intestine
    • chylomicrons
  26. Some clinical manifestations of hyperlipidemia
    • Lipemia retinalis
    • Cutaneous xanthomas
    • Tuberous xanthomas
    • Palmar crease xanthomas
  27. Familial Hypercholesterolemia (FH)
    • Elevated total cholesterol
    • >300 mg/dL in adults
    • >250 mg/dL in children

    Autosomal dominant inheritance
  28. LDL receptor functions via receptor-mediated endocytosis
    high cholesterol plasma level -> high LDL uptake -> high cholesterol cytosol level -> down regulation of cholesterol synthesis

    • SREBP/SCAP
    • HMGR
  29. LDL-R deficiency -> FH
    • receptor is not produced
    • receptor is not translocated to cell surface
    • receptor doesn't bind LDL
    • receptor doesn't cluster/endocytosis
  30. PCSK9 is a normal human protein that binds the LDL receptor promotes LDLR degradation in lysosomes
    potential drug target

Card Set Information

Author:
akhan
ID:
316263
Filename:
Biochem - Unit II - cholesterol
Updated:
2016-02-21 22:02:31
Tags:
biochemistry cholesterol
Folders:
biochemistry
Description:
Biochem - Unit II - cholesterol - Suzuki
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