Cholesterol Metabolism Notes

Cholesterol Metabolism

Overview

• Cholesterol is a vital constituent of all human cells.
• It is essential for:
  • Cell membrane synthesis
  • Steroid hormone production
  • Bile acid synthesis
  • Vitamin D synthesis

Sources of Cholesterol

• Cells primarily obtain cholesterol from:
  • Low-Density Lipoproteins (LDL)
  • High-Density Lipoproteins (HDL)
• De novo synthesis:
  • Occurs in the liver.
  • Driven by acetyl CoA and ATP.

De Novo Synthesis

• Citrate Shuttle:
  • Transports mitochondrial acetyl CoA to the cytoplasm.
  • This is where the synthesis takes place.
• NADPH:
  • Supplied by the pentose phosphate pathway (PPP).
  • Provides reducing equivalents necessary for the synthesis.

Mevalonic Acid Synthesis

• Location:
  • Smooth Endoplasmic Reticulum (SER)
• Rate-Limiting Step:
  • The synthesis of mevalonic acid is the crucial, rate-limiting step in cholesterol biosynthesis.
• Enzyme:
  • Catalyzed by HMG CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase).

Regulation of Cholesterol Synthesis

• Feedback Inhibition:
  • Increased cholesterol levels can inhibit further synthesis.
  • This is done through a feedback inhibition mechanism.
• Hormonal Influence:
  • Insulin promotes cholesterol synthesis.
• Gene Expression:
  • Control over de novo cholesterol synthesis is also dependent on regulation of HMG CoA reductase gene expression in the cell.

Specialized Enzymes

• Key Enzymes:
  • Lecithin Cholesterol Acyltransferase (LCAT)
  • Cholesteryl Ester Transfer Protein (CETP)

LCAT

• Function:
  • LCAT is found in the bloodstream.
  • Activated by HDL apoproteins.
  • Adds a fatty acid to cholesterol.
• Product:
  • Produces soluble cholesterol esters (e.g., in HDL).

CETP

• Function:
  • Transfers cholesteryl esters from HDL to other lipoproteins like IDL (Intermediate-Density Lipoprotein).
  • IDL then becomes LDL by acquiring these cholesteryl esters.
  • The cholesteryl ester transfer protein (CETP) facilitates this transfer process.