Cholesterol Metabolism

Cholesterol Metabolism Notes

Lecture Overview

• Instructor: J. Scott Pattison, Ph.D.

• Office: Lee Med Bldg, Room 210

• Email: james.pattison@usd.edu

• Date: March 19th, 2025

Objectives of Cholesterol Metabolism

1. Describe the roles of cholesterol in the body.

2. Understand the biosynthetic pathway of cholesterol through HMG-CoA reductase.

3. Discuss the regulation of cholesterol biosynthesis.

4. Explain the structure, synthesis, and metabolism of plasma lipoproteins.

5. Recognize the roles of various apolipoproteins.

6. Describe the etiology and pathology of common hyperlipoproteinemias.

7. Explain treatments for high serum cholesterol using diet and medication.

Sources of Cholesterol

• Sources:

  • Diet: Derived from food.

  • Endogenous: Synthesized within the body.

• Medication: VYTORIN is used to treat both sources.

Functions of Cholesterol

• Membrane Fluidity: Cholesterol reduces membrane fluidity while preventing crystal formation of phospholipids.

• Vitamin D3 Synthesis: Involved in calcium absorption.

• Steroid Hormone Synthesis: Precursor for sex steroids and adrenal hormones.

• Bile Salts: Major end product of cholesterol metabolism, aiding in digestion.

Role in Membrane Fluidity

1. Reduces fluidity and permeability in cellular membranes.

2. Restricts the movement of phospholipids, preventing solid behavior.

3. Constitutes 25%-40% of plasma membrane lipids.

Vitamin D3 Synthesis

• Conversion:

  • 7-dehydrocholesterol is converted to pre-vitamin D3 in skin via UV light.

  • Hydroxylation: Occurs in the liver and kidneys to yield Calcitriol, an active form of Vitamin D3.

• Functions of Calcitriol: Regulates minerals (Ca, Mg) and promotes bone health.

Steroid Hormone Synthesis

• Tissues Involved: Liver, adrenals, gonads, intestine, placenta.

• Regulation: Cholesterol synthesis is regulated based on dietary intake.

• Pathway Overview: Cholesterol (C27) to Pregnenolone (C21) to various steroid hormones.

Bile Salt Synthesis

• Function: Emulsifies dietary lipids aiding in their digestion.

• Synthesis and Storage: Made in the liver, stored in the gallbladder, and secreted into the intestine.

• Reabsorption: Enterohepatic recirculation of bile acids.

Biosynthesis of Cholesterol - Overview

1. Sources of Acetyl CoA: From citrate in the cytoplasm.

2. Stages:

   • Stage 1: Acetyl CoA → Mevalonate via HMG-CoA reductase (key regulatory step).

   • Stage 2: Mevalonate → Isoprenoid intermediates (isopentenyl PP).

   • Stage 3: Isoprenoid steps to Squalene.

   • Stage 4: Squalene to Cholesterol (C27).

Regulation of Cholesterol Biosynthesis

• Transcriptional Control: SREBP regulates HMG-CoA reductase transcription based on cholesterol levels.

• Degradation Regulation: High cholesterol leads to degradation of HMG-CoA reductase.

• Phosphorylation Effects: HMG-CoA reductase is inactivated through phosphorylation. Insulin promotes its activation.

Cholesterol Transport and Lipoproteins

• Types of Lipoproteins:

  • Chylomicrons: Transport dietary fat from the intestine.

  • VLDL: Transport endogenous fat from the liver.

  • LDL: Delivers cholesterol to tissues.

  • HDL: Reverse cholesterol transport back to the liver.

• Structure: Composed of a core of nonpolar lipids surrounded by phospholipids and apolipoproteins.

Hyperlipoproteinemias

• Definition: Excess of lipoproteins due to metabolic disorders.

• Types: Familial hypercholesterolemia and its various classifications based on receptor defects and metabolic impacts.

Treatment of High Cholesterol

1. Statins: e.g., Lipitor inhibit HMG-CoA reductase.

2. Cholesterol Absorption Inhibitors: e.g., Ezetimibe and Cholestyramine.

3. Niacin: Increases HDL levels.

4. Monitoring Levels:

   • Desirable Total Cholesterol: <200 mg/dL

   • HDL: >60 mg/dL is protective.

Cholesterol Homeostasis

• LDL Receptors: Critical for regulating cholesterol uptake from circulation to maintain homeostasis.

• Accumulation from ineffective uptake can lead to arterial plaque formation.

Conclusion and Questions

• Open floor for any queries regarding cholesterol metabolism, its roles, transport, or treatment strategies.