Understanding Cholesterol Metabolism

Importance of Cholesterol

• Cholesterol is a basic unit for:
  • Bile salts: Aid in the emulsification of large fat globules.
  • Steroid hormones: Includes testosterone, progesterone, estrogen, aldosterone, and cortisol.
  • Packaged into lipoproteins for transport.
  • Integral component of cell membranes.

Cholesterol Synthesis Overview

• Location: Primarily in the liver.
• Pathways:
  • Exogenous: Ingestion of food, transported via chylomicrons.
  • Endogenous: Synthesis within the liver.

Metabolic Pathways

1. Glycolysis: Glucose → Pyruvate
2. Pyruvate to Acetyl-CoA: Enters Krebs cycle, producing NADH, FADH2, and ATP.
3. Excess Acetyl-CoA:
   • Ketogenesis: Forms ketone bodies for the brain and muscles.
   • Cholesterol synthesis.

Detailed Cholesterol Synthesis Steps

1. Acetyl-CoA to Acetoacetyl-CoA
   • Enzyme: Thiolase
   • Reaction: 2 Acetyl-CoA → Acetoacetyl-CoA
2. Formation of HMG-CoA
   • Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA
   • Enzyme: HMG-CoA Synthase
3. Conversion to Mevalonate
   • Enzyme: HMG-CoA Reductase (Rate-limiting step)
   • Inhibition: Statins (e.g., Lipitor), high levels of cholesterol
   • NADPH needed for reduction
4. From Mevalonate to Isopentenyl Pyrophosphate
5. Formation of Squalene
   • 21 steps from Isoprene units to Squalene
   • Enzyme: Squalene Synthase
6. Squalene to 7-Dehydrocholesterol
7. 7-Dehydrocholesterol to Cholesterol

Functions of Cholesterol

1. Cell Membrane Incorporation
   • Reduces fluidity.
   • Prevents phase transitions.
   • Combines with glycosphingolipids to form lipid rafts for signaling.
2. Synthesis of Steroid Hormones
   • Testosterone, Estrogen, Progesterone, Cortisol, Aldosterone.
3. Formation of Bile Salts
   • Cholic acid and Deoxycholic acid for the emulsification of lipids.
4. Packaging into Lipoproteins
   • Enzyme: ACAT (Acyl-CoA Cholesterol Acyltransferase)
   • Forms cholesterol esters for transport in LDL, VLDL, and HDL.

Regulation of Cholesterol Synthesis

• Insulin: Stimulates HMG-CoA Reductase.
• Glucagon: Inhibits HMG-CoA Reductase.
• Cholesterol: Feedback inhibition via proteolytic enzymes.

Conclusion

• Understanding cholesterol metabolism involves linking its synthesis, transport, and functional roles in the body.
• Regulation is crucial due to cholesterol’s roles in critical biological processes.
• Common medications target key enzymes to manage cholesterol levels.

Key Enzymes to Remember

• Thiolase
• HMG-CoA Synthase
• HMG-CoA Reductase (Rate-limiting, regulated by statins)
• ACAT