Cholestrol synthesis

About 20% of total daily cholesterol production occurs in the liver; other sites of higher synthesis rates include the intestines, adrenal glands, and reproductive organs.

Synthesis within the body starts with the mevalonate pathway where two molecules of acetyl CoA condense to form acetoacetyl-CoA.

The four-ring nucleus of cholesterol is cyclopentanoperhydrophenanthrene ring (Note not benzene ring; animals cannot synth benzene ring)

2. Distribution: All cells- and synthesized from acetic acid in animal tissue. Liver and intestinal mucosa.

1. Acetyl-CoAs are converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)

2. HMG-CoA is converted to mevalonate

3. Mevalonate is converted to the isoprene based molecule, isopentenyl pyrophosphate (IPP), with the concomitant loss of CO2

4. IPP is converted to squalene

5. Squalene is converted to cholesterol.

HMGR; is the primary chol. Reg mechanism; The enzyme is controlled by four distinct mechanisms: feed-back inhibition, control of gene expression, rate of enzyme degradation and phosphorylation-dephosphorylation.

Cholesterol acts as a feed-back inhibitor of pre-existing HMGR as well as inducing rapid degradation of the enzyme. The latter is the result of cholesterol-induced polyubiquitination of HMGR and its degradation in the proteosome

HMGR is also covalently modified as a result of phosphorylation and dephosphorylation. The enzyme is most active in its unmodified form. Phosphorylation of the enzyme decreases its activity.

HMGR is phosphorylated by AMP-activated protein kinase,

Proteolytic Regulation of HMG-CoA Reductase

The amount of HMGR is regulated by the rate of flux through the mevalonate synthesis pathway changes.

When the flux is high the rate of HMGR degradation is also high. When the flux is low, degradation of HMGR decreases. This phenomenon can easily be observed in the presence of the statin drug

HMGR is localized in the ER and contains a sterol-sensing domain, SSD. When sterol levels increase in cells there is corresponding increase in the rate of HMGR degradation .

Regulation of HMGR by covalent modification

HMGR is most active in the dephosphorylated state. Phosphorylation is catalyzed by AMP-activated protein kinase, AMPK, (used to be termed HMGR kinase), an enzyme whose activity is also regulated by phosphorylation. Phosphorylation of AMPK is catalyzed by AMPK kinase (AMPKK).

Hormones such as glucagon and epinephrine negatively affect cholesterol biosynthesis by increasing the activity of the inhibitor of phosphoprotein phosphatase inhibitor-1, PPI-1.

Insulin stimulates the removal of phosphates and, thereby, activates HMGR activity. Additional regulation of HMGR occurs through an inhibition of its' activity as well as of its' synthesis by elevation in intracellular cholesterol levels.

Clinical Significance of Bile Acid Synthesis

Bile acids perform four physiologically significant functions:

1. their synthesis and subsequent excretion in the feces represent the only significant mechanism for the elimination of excess cholesterol.

2. bile acids and phospholipids solubilize cholesterol in the bile, thereby preventing the precipitation of cholesterol in the gall bladder.

3. they facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents that render fats accessible to pancreatic lipases.

4. they facilitate the intestinal absorption of fat-soluble vitamins.