CHOLESTEROL
BIOSYNTHESIS
RA NGALA
Summary of Cholesterol biosynthesis
Regulation of cholesterol biosynthesis
• Cellular supply of cholesterol is maintained at a steady
level by three distinct mechanisms:
1. Regulation of HMGR activity and levels
2. Regulation of excess intracellular free cholesterol through
the activity of acyl-CoA:cholesterol acyltransferase,
ACAT
3. Regulation of plasma cholesterol levels via LDL receptor-
mediated uptake and HDL-mediated reverse transport
4. Utilization of cholesterol.
5. Regulation of cellular sterol content
• 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.
Biosynthesis of bile salts
Biosynthesis of secondary bile salts
• 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.
