Biosynthesis of Cholesterol

Biosynthesis of Cholesterol

Functions of Cholesterol

  • Component of mammalian cell membranes: Cholesterol contributes to the fluidity and structural integrity of cell membranes.
  • Precursor of important biomolecules:
    • Bile acids: Necessary for fat digestion and absorption.
    • Steroid hormones: Hormones like cortisol, aldosterone, and sex hormones.
    • Vitamin D: Essential for calcium metabolism and bone health.

Disorders of Cholesterol Metabolism

  • Cardiovascular Disease: High levels of cholesterol can lead to atherosclerosis.
  • Gallstones: Often formed from excess cholesterol; not visible on X-ray but detectable via ultrasound (cholecystogram).

Sources of Cholesterol in the Body

  • Synthesis: Approximately 70% synthesized within the body, primarily in the liver.
  • Diet: About 30% obtained from dietary sources, exclusively from animal products such as:
    • Eggs
    • Meat
    • Milk
    • Average Western diet contains 500-2000 mg/day.

Site of Cholesterol Synthesis

  • Main site of synthesis: Liver
  • Other sites: Intestine, adrenal cortex, gonads.

Structure of Cholesterol

  • Complex steroid structure, which is crucial for its function in membranes and as a precursor for other molecules.

Energetic Cost of Cholesterol Production

  • Requires:
    • 18 moles of acetyl CoA
    • 18 moles of ATP
    • 16 moles of NADPH

Stages of Synthesis of Cholesterol

  1. Acetyl-CoA to Mevalonate:

    • Enzyme: HMG-CoA Reductase.
    • Occurs in the cytosol.
    • Coenzymes: NADPH.

  2. Mevalonate to Active Isoprenoid Units:

    • Forms Farnesyl pyrophosphate.
    • Enzymes: Kinase and decarboxylase, using ATP and magnesium.
    • Precursor for Ubiquinone (CoQ10).

  3. Farnesyl pyrophosphate to Squalene:

    • Two molecules of farnesyl pyrophosphate condense to form squalene.
    • Enzyme: Squalene Synthase (found in the endoplasmic reticulum).
    • Coenzymes: NADPH, Mg, Mn.

  4. Squalene to Lanosterol:

    • Uses oxygen and NADPH.
    • Enzyme: Squalene Monooxygenase.

  5. Lanosterol to Cholesterol:

    • Involves reductions and decarboxylations.
    • Enzyme: Reductase.

Factors Influencing Cholesterol Regulation

  • Factors increasing free cholesterol concentration:
    • Increased biosynthesis.
    • Hydrolysis of cholesterol esters.
    • Dietary intake and uptake from chylomicrons.
  • Factors decreasing free cholesterol concentration:
    • Inhibition of cholesterol biosynthesis.
    • Downregulation of LDL receptors.
    • Conversion of cholesterol into bile acids or steroid hormones.

Regulation of HMG-CoA Reductase

  • Allosteric Enzyme:
    • Inhibition: Glucagon, cortisol, high cholesterol levels.
    • Activation: Insulin and thyroid hormones (primary hormone is insulin).

Attempts to Lower Cholesterol in Humans

  • Varying results from dietary changes:
    • Low dietary cholesterol can influence cholesterol synthesis rates.

Lifestyle Effects that Elevate Blood Cholesterol

  • Factors include:
    • High blood pressure
    • Smoking
    • Male gender
    • Abdominal obesity
    • Lack of exercise

Drugs that Lower Cholesterol

  • Statin drugs: Inhibit HMG-CoA Reductase, examples include:
    • Lipitor
    • Zocor
    • Provachol
  • Important to supplement with CoQ10 due to statin side effects (recommended dose: 100 mg/day).

Bile Acids

  • Synthesized in liver from cholesterol, mainly cholic and chenodeoxycholic acid.
  • Function: Aid in digestion of dietary fats by emulsifying them.
  • Reabsorption: Up to 98% of bile acids are reabsorbed during enterohepatic circulation.

Cholesterol Metabolism and Excretion

  • Cholesterol cannot be digested; elimination occurs via feces, primarily as bile acids and cholesterol (converted to coprostanol by bacteria).

Natural Remedies to Lower Cholesterol

  • Vitamin C: Facilitates conversion of cholesterol to bile acids.
  • Bran: Binds cholesterol and bile acids, promoting their excretion.