Cholesterol Synthesis and Lipid Metabolism Notes

Introduction to Cholesterol Synthesis

• Liver Function: The liver is the primary organ responsible for cholesterol synthesis, although other cells and tissues can also produce cholesterol.
• Cholesterol's Role: It serves as a precursor to various steroid hormones.

Biosynthesis of Cholesterol

• Location: Occurs in all tissues, predominantly the liver.
• Molecular Composition: Cholesterol contains 27 carbon atoms.
  • Key Components:
  • Acetyl CoA: A 2-carbon building block.
  • NADPH: Involved in redox reactions.
  • Enzymes: Various enzymes facilitate the synthesis process.

Mechanism of Synthesis

• Anabolic Process: Cholesterol biosynthesis is an anabolic process requiring energy.
• Enzyme Locations: Enzymes involved are located in the cytosol and the endoplasmic reticulum (ER).
• Regulation of Synthesis:
  • Initiated when cellular cholesterol levels are low.
  • Involves numerous enzyme-catalyzed steps.
  • Feedback Mechanism: Once sufficient cholesterol levels are achieved, synthesis is inhibited. Cholesterol provides negative feedback to pathway enzymes.

Key Steps in Cholesterol Synthesis

1. Formation of Acetoacetyl CoA:

   • Two molecules of acetyl CoA condense to form acetoacetyl CoA.
   • Enzyme: β-Ketothiolase.

2. Conversion to HMG CoA:

   • Acetoacetyl CoA combines with another acetyl CoA to form HMG CoA.
   • Enzyme: HMG-CoA synthase, which also plays a role in ketone body synthesis.

3. Mevalonate Synthesis:

   • HMG CoA is reduced to mevalonate, the rate-limiting step in cholesterol biosynthesis.
   • Enzyme: HMG CoA reductase, which is inhibited by statins.
   • Mevalonate is further processed into isopentenyl pyrophosphate (IPP), also known as an isoprene unit.

4. Isoprene Unit Creation:

   • Mevalonate is converted to 5-pyrophosphomevalonate by enzymes.
   • Decarboxylation of this compound produces isopentenyl pyrophosphate (IPP).

5. Conversion to Lanosterol:

   • IPP is used in the synthesis of squalene.
   • Squalene is then converted to lanosterol, the steroid core.

6. Lanosterol to Cholesterol:

   • Lanosterol undergoes several reactions to finally form cholesterol.
   • Cholesterol can be converted to cholesterol esters through the enzyme acyl CoA cholesterol acyltransferase (ACAT), which assists in the storage and protection of cholesterol.

Clinical Relevance of Statins

• Purpose of Statins: Prescribed to lower cholesterol levels.
• Mechanism: Statins act as competitive inhibitors of HMG CoA reductase, suppressing cholesterol synthesis.
• Health Benefits: Lowering cholesterol levels is crucial for improving heart health.

Fatty Acid Storage

• Fatty acids are esterified with glycerol to form triacylglycerols (TAGs).
• Tag's Importance: TAGs serve as the storage form of fatty acids in the body.
• The liver and adipose tissue synthesize glycerol 3-phosphate, facilitated by the enzyme glycerol 3-phosphate dehydrogenase, from dihydroxyacetone phosphate.