In-depth Notes on Cholesterol and Lipoproteins

Introduction to Medical Sciences

  • Dr. Karen Porter discusses membrane, lipids, and signaling in the context of cholesterol and lipoproteins.

Lecture Overview

  • Lecture 1: Cell membrane and structure
  • Lecture 2: Membrane transport
  • Lecture 3: Cell signaling
  • Lecture 4: Cholesterol and lipoproteins
  • Tutorial: Membranes

Learning Objectives

  • List main types of lipids in the body:
    • Triglycerides, cholesterol, phospholipids, steroids.
  • Classify lipoproteins and understand differences:
    • Chylomicrons, VLDL, LDL, HDL.
  • Understand lipid transport between intestines, liver, and peripheral cells.
  • Know the steps of atheroma development and their effects on different organs.
  • Understand statin mechanisms, including pleiotropic effects.
  • Learn about the causes of familial hypercholesterolaemia (FH).

Functions of Lipids

  • Energy storage.
  • Major components of cell membranes.
  • Signaling molecules.
  • Required to solubilize fat-soluble vitamins.
  • Biosynthetic precursors for steroid hormones (derived from cholesterol).

Cholesterol Transport

  • Sources:
    • 25% from the diet or synthesized in the liver.
  • Cholesterol is insoluble in blood plasma; it is transported by lipoproteins.

Lipoproteins

  • Function: Main means of lipid transport in blood (both triglycerides and cholesterol).
  • Structure: Share a general structure, varying in protein-to-lipid ratios based on density and chemical properties.
    • Categories:
    • Chylomicrons: Transport dietary fats from intestines.
    • VLDL: Transport lipids made in the liver to tissues.
    • LDL: Main cholesterol carrier; delivers cholesterol to peripheral tissues.
    • HDL: Transports cholesterol back to the liver.

Structure of Lipoproteins

  • External Monolayer: Contains phospholipids, cholesterol, and apolipoproteins.
  • Core: Contains cholesterol esters and triacylglycerols.

Apolipoproteins

  • ApoA: In HDL, mediates cholesterol efflux from cells to the liver.
  • ApoB: Facilitates LDL uptake by recognizing receptors.
  • ApoC: Activates lipoprotein lipase; transferred between lipoproteins.
  • ApoE: Stabilizes VLDL for uptake and is a ligand for LDL receptors.

Synthesis and Regulation of Apolipoproteins

  • Synthesis: Regulated by dietary fat intake and controlled by hormones (insulin, glucagon, sex hormones) and drugs (statins, alcohol).
  • Apolipoproteins regulate key enzymes in lipoprotein metabolism and ensure targeting to the correct tissues.

LDL Receptor Mechanism

  • Mechanism: Binds LDL (contains apoB100 or apoE), internalizes LDL, and recycles the receptor.
  • High cholesterol in cells suppresses LDL receptor production, preventing excessive uptake of LDL, leading to elevated blood LDL levels.

HDL Overview

  • Known as "Good Cholesterol."
  • High HDL levels correlate with low atherosclerosis incidence.
  • Functions include cholesterol scavenging and transport back to the liver (Reverse Cholesterol Transport).

Familial Hypercholesterolemia (FH)

  • Mutation in LDL receptor leads to high LDL levels in blood due to poor uptake.
  • Increased risk of atherosclerosis.
  • Other genetic defects related to apolipoproteins can lead to similar issues.

Cholesterol and Atherosclerosis

  • Cholesterol is crucial for cell membrane structure, and synthesis of bile acids, hormones, and fat-soluble vitamins.
  • High serum cholesterol levels indicate increased cardiovascular disease risk.
  • Atherosclerotic plaques are often cholesterol-rich, particularly from LDL.

Clinical Manifestations

  • Cardiac: Chest pain, heart attack.
  • Cerebral: Stroke, cerebral hemorrhage.
  • Peripheral: Ischemia, ulceration, gangrene.

Atheroma Development and Symptoms

  1. Fatty streak formation leading to plaque development.
  2. Fibrous plaques leading to narrowed arteries.
  3. Advanced plaque can cause complete occlusion.

Cholesterol Synthesis and Regulation

  • Cholesterol synthesis primarily occurs in the liver and intestines.
  • Statins inhibit HMG-CoA reductase, leading to lower cholesterol production and increased LDL receptor expression.

Statins

  • Statins lower blood cholesterol by inhibiting cholesterol synthesis in the liver, leading to enhanced uptake of LDL from blood.
  • Pleiotropic effects include improved endothelial function and reduced inflammation.

PCSK9 and Cholesterol Regulation

  • PCSK9 is a protease enzyme involved in lipid metabolism, linking mutations to coronary heart disease.
  • Inhibition of PCSK9 increases LDL receptor levels, enhancing clearance of LDL from circulation.

References

  • Further Reading:
    • Medical Sciences (Naish, 2nd edition)
    • Lipid metabolism Biochemistry – Instant Notes (BD Hames & NM Hooper)