Cholesterol Metabolism

• • Cholesterol is synthesized from cytosolic acetyl coenzyme A (CoA) by a sequence of reactions.
  • Glucose is a major source of carbon for acetyl CoA
  • Cytosolic acetyl CoA forms acetoacetyl CoA, which condenses with another acetyl CoA to form hydroxymethylglutaryl CoA (HMG-CoA)

 

• Acetyl CoA undergoes similar reactions in the mitochondrion, where HMG-CoA is used for ketone body synthesis.

• Cytosolic HMG-CoA, a key intermediate in cholesterol biosynthesis, is reduced in the endoplasmic reticulum to mevalonic acid by the regulatory enzyme HMG-CoA reductase.

 

• • • HMG-CoA reductase is inhibited by cholesterol.

 

• HMG-CoA reductase is also inhibited by phosphorylation by the adenosine monophosphate (AMP)-activated protein kinase.

 

• • • In the liver, HMG-CoA reductase is
      • inhibited by bile salts

 

• induced when blood insulin levels are elevated.

• Mevalonic acid is phosphorylated and decarboxylated to form the five-carbon (C-5) isoprenoid, isopentenyl pyrophosphate

 

• • Two isopentenyl pyrophosphate units condense, forming a C 10 compound, geranyl pyrophosphate, which reacts with another C-5 unit to form a C-15 compound, farnesyl pyrophosphate
  • Squalene is formed from two C-15 units and then oxidized and cyclized, forming lanosterol
  • Lanosterol is converted to cholesterol in a series of steps
  • The ring structure of cholesterol cannot be degraded in the body.
    • The bile salts in the feces are the major form in which the steroid nucleus is excreted.
  • Bile salts

 

• synthesized in the liver from cholesterol

 

• • • An alpha-hydroxyl group is added to carbon 7 of cholesterol.
      • Catalyzed by 7a-hydroxylase
        • inhibited by bile salts
        • catalyzes this rate-limiting step.
    • The double bond of cholesterol is reduced, and further hydroxylations occur,
      • The bile acid with hydroxyl groups at positions 3 and 7 is chenocholic acid.
      • The bile acid with hydroxyl groups at positions 3, 7, and 12 is cholic acid.

 

• These bile acids each have a pK of about 6.

 

• • • • Above pH 6, the molecules are salts (i.e., they ionize and carry a negative charge).
      • At pH 6 (the pH in the intestinal lumen), half of the molecules are ionized and carry a negative charge.
      • Below pH 6, the molecules become protonated, and their charge decreases as the pH is lowered.
    • Conjugation of the bile salts
      • The bile salts are activated by ATP  and coenzyme A,forming their
      • CoA derivatives, which can form conjugates with either glycine or taurine.
      • Glycine
        • an amino acid, forms an amide with the carboxyl group of a bile salt, forming glycocholic acid or glycochenocholic acid.
        • These bile salts each have a pK of about 4.
        • This pK is lower than the unconjugated bile salts, so the conjugated bile salts are more completely ionized at pH 6 in the gut lumen and serve as better detergents.
      • Taurine
        • is derived from the amino acid cysteine
        • forms an amide with the carboxyl group of a bile salt.

 

• Because of the sulfite group on the taurine moiety, the taurocholic and taurochenocholic acids have a pK of about 2.

 

• • • • • They ionize very readily in the gut and are the best detergents among the bile salts.
    • Fate of the bile salts

 

• Primary bile salts.

• Cholic acid, chenocholic acid, and their conjugates are known as the primary bile salts.

 

• • • • • They are made in the liver
        • secreted via the bile through the gallbladder into the intestine because they are amphipathic they aid in lipid digestion.
        • In the intestine, bile salts can be deconjugated and dehydroxylated (at position 7 ) by intestinal bacteria.
    • Secondary bile salts.
      • Bile salts are resorbed in the ileum and return to the liver, where they can be reconjugated with glycine or taurine.
      • However, they are not rehydroxylated.
      • Those that lack the 7a- hydroxyl group are called secondary bile salts
      • The liver recycles about 95% of the bile salts each day;5% are lost in the feces.

Applied aspects

• • Statins
    • competitive inhibitors of HMG-CoA reductase
    • reduce the serum level of cholesterol

 

• Ursodeoxycholate in cholesterol Gallstones

 

• • • inhibit the formation of cholesterol gallstones.

 

• It is a hydrophilic bile salt that decreases the content of cholesterol in bile.

 

• cholestyramine
  • Bile acid sequestrants
  • bind with bile acids in the intestinal lumen.
  • The insoluble complex of bile acid sequestrant and bile acid is eliminated in the stool.
  • This causes fecal loss of cholesterol.
  • As the body loses dietary cholesterol, the cells take up low-density lipoprotein (LDL) from circulation, which results in a lowering of circulating cholesterol.LINICAL