Philip_Cholesterol Metabolism BCC

Learning Objectives

  • Recognize the chemical structure of cholesterol and identify basic building blocks.

  • Describe sources of cholesterol:

    • Dietary intake: eggs, beef, poultry, cheese.

    • De novo synthesis: liver, extrahepatic tissues.

  • Define physiological significance and role of cholesterol:

    • Crucial for cell membranes, bile salts, steroid hormones, vitamin D.

    • Excessive levels linked to heart disease.

  • List the 4 steps of cholesterol biosynthesis.

  • Explain regulation of cholesterol synthesis.

  • Define mechanism of statins and relevant clinical pearls.

  • List three main uses of synthesized cholesterol.

  • Discuss role of bile acids, biliary cholesterol, and cholesterol esters.

  • Describe common biological molecules cholesterol esters are precursors for.

  • Explain LDL metabolism and target drug therapies.

Physiological Roles of Cholesterol

  • Cell Membranes: Essential component, only found in animal cells.

  • Precursors:

    • Bile Salts: Aid in fat digestion.

    • Steroid Hormones: Include sex hormones, adrenal hormones.

    • Vitamin D: Synthesized from cholesterol.

  • Lipoproteins: Major component for lipid transport.

  • Health Implications: High cholesterol levels lead to heart disease.

Cholesterol Structure

  • Composition:

    • Steroid Nucleus: 4 hydrocarbon rings.

    • Branch Chain: Hydrocarbon chain attached to the D ring.

    • Details:

      • 27 carbon atoms.

      • Hydroxyl group at C3.

      • Double bond between C5 and C6.

      • Highly non-polar.

Sources of Cholesterol

  1. Dietary Intake: Found in animal products (e.g., eggs, meat).

  2. De Novo Synthesis: Primarily in the liver.

  3. Other Tissues: Synthesis in extrahipatic tissues.

Cholesterol Synthesis

  • Location: Cytoplasm or endoplasmic reticulum.

  • Energy Source: Hydrolysis of ATP and acetyl-CoA.

  • Carbon Source: All 27 carbons from acetyl-CoA.

  • Production: NADPH provides reducing power, with acetyl-CoA converted to citrate in mitochondria, then cleaved back to acetyl-CoA in the cytosol.

Cholesterol Synthesis Stages

  • Stage 1: Acetyl CoA --> HMG-CoA.

  • Key Enzyme: HMG-CoA reductase (rate-limiting step).

  • Feedback inhibitors: Cholesterol and mevalonate.

  • Completion: Transition through multiple stages, with squalene being a key intermediate leading to cholesterol.

Regulation of Cholesterol Synthesis

  • Key Regulator: HMG-CoA reductase.

  • Regulation Mechanisms:

    • Gene transcription and new protein synthesis.

    • Protein degradation via proteolysis.

    • Covalent modification (phosphorylation by AMPK).

    • Competitive inhibition (statins).

Regulation by Phosphorylation

  • Glucagon Activation: Increases AMPK activity leading to HMG-CoA reductase inactivation.

  • Insulin Activation: Promotes protein phosphatase that dephosphorylates and activates HMG-CoA reductase.

Regulation by Competitive Inhibition

  • Statins: Competitive inhibitors of HMG-CoA reductase; limit cholesterol synthesis, used for hypercholesterolemia.

  • Coenzyme Q10 Impact: Statin usage may decrease levels; supplements considered.

Cholesterol Metabolism Products

  • Secreted by Hepatocytes:

    • Cholesterol esters

    • Biliary cholesterol

    • Bile acids

Bile Acids

  • Formation: Synthesized from cholesterol in the liver; stored in the gallbladder for lipid digestion.

  • Characteristics: Amphipathic nature aids in emulsifying lipids in intestines.

Bile Salts and Biliary Cholesterol

  • Conjugation: Bile acids combined with amino acids for excretion.

  • Efficacy: More effective for cholesterol excretion than bile acids.

Cholesterol Esters

  • Nature: Majority of cholesterol exists as esters; attached long-chain fatty acid increases hydrophobicity.

  • Function: Not part of membranes; transport form packaged into lipoproteins (VLDL, LDL) for tissue delivery.

Steroid Hormones

  • Source: All classes of steroid hormones are cholesterol-derived.

  • Synthesis Locations: Adrenal cortex, gonads, placenta.

Vitamin D

  • Sources: Obtained through dietary means or synthesized from cholesterol precursors.

VLDL Metabolism

  • Production: Synthesized in liver.

  • Transport Role: Delivers triglycerides (TAGs) to tissues.

  • Hydrolysis: Lipoprotein lipase hydrolyzes TAGs into fatty acids and glycerol.

  • Conversion: Remnants can form IDL or be converted to LDL.

LDL Metabolism

  • Binding Mechanism: LDL binds to specific receptors, followed by endocytosis.

  • Degradation Products: Free cholesterol, fatty acids, amino acids, phospholipids.

  • PCSK9 Role: Binds to LDL receptors, increasing degradation of receptors; inhibitors allow more receptors to clear LDL from bloodstream (e.g., Alirocumab, Evolocumab).