Cholesterol Metabolism
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- 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.
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- HMG-CoA reductase is inhibited by cholesterol.
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- HMG-CoA reductase is also inhibited by phosphorylation by the adenosine monophosphate (AMP)-activated protein kinase.
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- In the liver, HMG-CoA reductase is
- inhibited by bile salts
- In the liver, HMG-CoA reductase is
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- induced when blood insulin levels are elevated.
- Mevalonic acid is phosphorylated and decarboxylated to form the five-carbon (C-5) isoprenoid, isopentenyl pyrophosphate
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- 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
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- An alpha-hydroxyl group is added to carbon 7 of cholesterol.
- Catalyzed by 7a-hydroxylase
- inhibited by bile salts
- catalyzes this rate-limiting step.
- Catalyzed by 7a-hydroxylase
- 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.
- An alpha-hydroxyl group is added to carbon 7 of cholesterol.
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- These bile acids each have a pK of about 6.
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- 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.
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- Because of the sulfite group on the taurine moiety, the taurocholic and taurochenocholic acids have a pK of about 2.
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- They ionize very readily in the gut and are the best detergents among the bile salts.
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- Fate of the bile salts
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- Primary bile salts.
- Cholic acid, chenocholic acid, and their conjugates are known as the primary bile salts.
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- 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.
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- 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.
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Applied aspects
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- Statins
- competitive inhibitors of HMG-CoA reductase
- reduce the serum level of cholesterol
- Statins
- Ursodeoxycholate in cholesterol Gallstones
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- inhibit the formation of cholesterol gallstones.
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- 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