5 metabolism of cholesterol

• Metabolism of cholesterol


  Cholesterol is found exclusively in animals
• The total body content of cholesterol in an adult man weighing 70 kg is about 140 g
• Cholesterol is amphipathic in nature
• Functions of cholesterol


  Structural component of cell membrane<|>Precursor for synthesis of all other steroids<|>Essential ingredient in structure of lipoproteins<|>Fatty acids transported to liver as cholesteryl esters for oxidation
• About 1 g of cholesterol is synthesized per day in adults
• Almost all tissues of the body participate in cholesterol biosynthesis
• The largest contribution to cholesterol biosynthesis is made by the liver (50%)
• Acetate of acetyl CoA provides all the carbon atoms in cholesterol
• The reducing equivalents for cholesterol synthesis are supplied by NADPH
• ATP provides energy for cholesterol synthesis
• For the production of one mole of cholesterol, 18 moles of acetyl CoA, 36 moles of ATP, and 16 moles of NADPH are required
• Synthesis of cholesterol stages

  1. Synthesis of HMG CoA

  2. Formation of mevalonate

  3. Production of isoprenoid units

  4. Synthesis of squalene

  5. Conversion of squalene to cholesterol
• Synthesis of HMG CoA

  1. Two moles of acetyl CoA condense to form acetoacetyl CoA

  2. Another molecule of acetyl CoA is added to produce HMG CoA
• HMG CoA reductase is the rate limiting enzyme in cholesterol biosynthesis
• HMG CoA reductase is present in endoplasmic reticulum
• HMG CoA reductase catalyses the reduction of HMG CoA to mevalonate
• Reducing equivalents for this reaction are supplied by NADPH
• Production of isoprenoid units

  1. Mevalonate is converted to 3-phospho 5-pyrophosphomevalonate

  2. Decarboxylation forms isopentenyl pyrophosphate (IPP)

  3. IPP isomerizes to dimethylallyl pyrophosphate (DPP)
• Synthesis of squalene


  1. IPP and DPP condense to produce geranyl pyrophosphate (GPP)

  2. Another molecule of IPP condenses with GPP to form farnesyl pyrophosphate (FPP)

  3. Two units of FPP unite and get reduced to produce squalene
• Conversion of squalene to cholesterol

  1. Squalene undergoes hydroxylation and cyclization utilizing O2 and NADPH to convert to lanosterol

  2. Formation of cholesterol from lanosterol is a multistep process with about 19 enzymatic reactions
• The penultimate product is 7-dehydrocholesterol which, on reduction, finally yields cholesterol
• 1. carbon isoprenoid units


  • dimethylallyl pyrophosphate (DPP)
  • isopentenyl pyrophosphate (IPP)
• Synthesis of squalene


  1. IPP and DPP condense to produce GPP

  2. Another IPP condenses with GPP to form FPP

  3. Two FPP units unite and get reduced to produce squalene
• Conversion of squalene to cholesterol

  1. Squalene undergoes hydroxylation and cyclization

  2. Formation of lanosterol

  3. Formation of cholesterol from lanosterol is a multistep process
• Important reactions in cholesterol formation

  • Reducing carbon atoms from 30 to 27
  • Removal of two methyl groups from C4
  • Removal of one methyl group from C14
  • Shift of double bond from C8 to C5
  • Reduction in the double bond between C24 and C25
• Cholesterol biosynthesis is part of a major metabolic pathway concerned with the synthesis of several other isoprenoid compounds
• Isoprenoid compounds derived from farnesyl pyrophosphate

  • Ubiquinone (coenzyme Q)
  • Dolichol
• HMG CoA reductase


  Rate limiting enzyme in cholesterol synthesis
• Feedback control in cholesterol synthesis

  1. Cholesterol controls its own synthesis

  2. Increase in cholesterol reduces synthesis of HMG CoA reductase
• Hormonal regulation of HMG CoA reductase

  1. Dephosphorylated form is more active

  2. Phosphorylated form is less active

  3. Glucagon and glucocorticoids favour inactive form

  4. Insulin and thyroxine increase active form
• Inhibition by drugs


  1. Compactin and lovastatin are competitive inhibitors

  2. They reduce cholesterol synthesis
• About 50 to 60% decrease in serum cholesterol level has been reported by a combined use of compactin and lovastatin
• HMG CoA reductase activity is inhibited by bile acids
• Fasting reduces the activity of HMG CoA reductase
• Forms of cholesterol in plasma lipoproteins

  • 70-75% in esterified form
  • 25-30% as free cholesterol
• Role of LCAT


  Responsible for transport and elimination of cholesterol from the body
• LCAT is synthesized by the liver
• Cholesterol ester forms an integral part of HDL
• Reverse cholesterol transport


  1. Cholesterol from peripheral tissues is trapped in HDL

  2. Transported to liver for degradation and excretion
• Hypercholesterolemia is an increase in plasma cholesterol (> 200 mg/dl)