Synthesis of Cholesterol

Lesson 23 : Fatty acid Degradation

Synthesis of Cholesterol

  1. Precursor of steroid hormones and bile salts.
  2. Most cholesterol is synthesized in liver cells, although most animal cells can synthesize it.
  3. Starts with 3 molecules of acetyl CoA to form 3-hydroxy-3-methyl-glutaryl CoA, which is reduced to mevalonate (C6) by HMG-CoA reductase (first committed step of cholesterol synthesis)
  4. Amount of cholesterol formation by liver and intestine is highly responsive to cellular levels of cholesterol.
  5. Enzyme HMG-CoA reductase is controlled in multiple ways:

    • Rate of enzyme synthesis is controlled by sterol regulatory element (SRE); SRE inhibits mRNA production
    • Translation of reductase mRNA is inhibited by nonsterol metabolites derived from mevalonate
    • Degradation of the enzyme occurs at high enzyme levels
    • Phosphorylation of enzyme
    • If enzyme is phosphorylated via glucagon pathway --> decreased activity--> cholesterol synthesis ceases when ATP levels are low

      If enzyme is dephosphorylated via insulin pathway --> increased activity

    Cells outside liver and intestine obtain cholesterol from blood instead of synthesizing it de novo.

  6. Steps in the uptake of cholesterol by LDL pathway:

    • apolipoprotein on surface of LDL particle binds to receptor on membrane of nonhepatic cells
    • LDL-receptor complex internalized by endocytosis
    • vesicles formed fuse with lysosomes, which breaks apart protein part of lipoprotein to amino acids and hydrolyzes cholesterol esters
    • released unesterified cholesterol can be used for membrane biosynthesis or be reesterified for storage

  7. Defects in LDL receptor lead to familial hypercholesterolemia (FH), in which cholesterol and LDL levels are markedly elevated.
  8. Result is deposition of cholesterol in tissues because of high levels of LDL-cholesterol in blood
  9. Heterozygotes suffer from atherosclerosis and increased risk of stroke
  10. Homozygotes usually die in childhood from coronary artery disease
  11. Disease is the result of an absence (homozygotes) or reduction (heterozygotes) in number of LDL receptors.
  12. LDL entry into liver and other cells is impaired.
  13. Drug therapy can help heterozygotes

    • can inhibit intestinal absorption of bile salts (which promote absorption of dietary cholesterol)
    • lovastatin - competitive inhibitor of HMG-CoA reductase ---> blocks cholesterol synthesis
Last modified: Monday, 23 January 2012, 7:08 AM