Lipoprotein Handling_RF2025

Barts and The London School of Medicine and Dentistry

  • Presentation Title: Lipoprotein Handling

  • Presenter: Dr. Robert Formosa

Learning Objectives

  • Describe the structure and composition of the main classes of lipoprotein, including very-low density lipoproteins (VLDL).

  • Outline the process of lipogenesis and its control.

  • Describe the role of lipoprotein lipase.

  • Discuss the role of low-density lipoproteins (LDL).

  • Describe the contribution of LDL to atherogenesis and clinical treatments to lower serum LDL-cholesterol levels.

  • Discuss the significance of high-density lipoproteins (HDL).

Topics to be Covered

  • Overview of lipoproteins

  • Lipoprotein lipase

  • Chylomicrons

  • LDLs

  • Cholesterol & CVD

  • HDLs

  • Atherosclerosis

  • Summary & learning objectives

What Are Lipoproteins?

  • Lipoproteins are particles of proteins and lipids found in plasma.

  • Functions:

    • Transport hydrophobic lipids: triacylglycerides (TAG/TG) & cholesterol between liver, intestine, and all body tissues.

    • Transported TAG depends on the body’s energy needs.

    • Transported cholesterol is part of an extracellular pool for cells.

  • Consequences of Mismanagement:

    • Potential development of atherosclerosis, cardiovascular disease, stroke, and peripheral vascular disease.

Importance of Lipoproteins

  • Global Causes of Death:

    • Cardiovascular diseases rank high among causes of death from 2000 to 2019.

  • Risk Factors:

    • Behavioral: Alcohol & drug use, dietary risks, tobacco smoke, low physical activity.

    • Metabolic: High body mass index, high systolic blood pressure, high total cholesterol, high fasting plasma glucose.

    • Environmental: Air pollution and various diseases (cirrhosis, diabetes, cancers).

Lipoprotein Overview

  • Majority of fatty acids come from diet in forms of triglycerides (90%), cholesterol, cholesterol esters, phospholipids, or free fatty acids.

  • Fatty acids can be synthesized in the liver during periods of excess energy intake.

  • Triglycerides and cholesterol are hydrophobic and cannot be transported in blood directly; they must be packaged in lipoprotein coats.

  • Lipoprotein Structure:

  • Outer Coat (Hydrophilic):

    • Phospholipids (amphiphatic), free cholesterol, and apoproteins.

  • Inner Core (Hydrophobic):

    • Contains cholesterol, cholesterol esters, triglycerides, and some vitamins (A and E).

Classes of Lipoproteins

  • Lipoproteins serve as transport systems for fats and cholesterols across various body systems, differing in size, fat content, and apoprotein types.

  • Key Lipoprotein Classes:

  • Chylomicrons: Formed in the gut, transport lipids from the GI to peripheral tissues.

  • VLDL: Formed in the liver, distribute triglycerides to peripheral tissues.

  • IDL: Result from partially absorbed VLDLs.

  • LDL: Deliver cholesterol from liver to peripheral cells.

  • HDL: Scavengers of excess cholesterol, returning it to the liver.

Chylomicron Metabolism

  • Chylomicrons are formed from absorbed fats and cholesterol in the GI tract, moving to the lymphatic system before entering blood.

  • Interact with HDL to receive ApoC2 and ApoE, crucial for determining their fate.

  • Functionality:

  • ApoC2: Activates triglyceride donation to peripheral cells.

  • ApoE: Permits remnant uptake by the liver.

VLDL Formation

  • Similar to chylomicron formation; produced in the liver and requires proteins from HDL.

  • VLDL remnants either re-absorbed by the liver or develop into LDL.

Lipoprotein Lipase (LPL)

  • Acts as the primary regulator for triglyceride transfer from VLDL and chylomicrons to target cells.

  • Functionality:

  • Breaks down triglycerides in chylomicrons and VLDLs into free fatty acids for cellular uptake.

  • Activity Regulation:

    • Highest in muscle during starvation (energy use) and in adipose cells post-meal (fat storage).

Low-Density Lipoproteins (LDL)

  • Function to deliver cholesterol to peripheral cells, formed as remnants of VLDL after triglyceride distribution.

  • IDLs transition to LDL via hepatic TAG ligase action.

  • Key Component:

  • ApoB100 enables receptor-mediated endocytosis in target cells.

Cholesterol Overview

  • Fundamental for cell membranes, steroid hormone biosynthesis, and bile acid formation.

  • Cells can synthesize cholesterol from acetyl CoA via HMG-CoA reductase.

  • Regulation:

  • High cholesterol levels induce negative feedback to reduce synthesis and uptake.

Cholesterol & Fat Metabolism Pathways

  • Key enzymes in the metabolic pathway from Acetyl-CoA to cholesterol.

High-Density Lipoprotein (HDL)

  • Functions include apoprotein exchange and reverse cholesterol transport.

  • Formation:

  • Produced by the liver as precursors (ApoA1 rich) that collect excess cholesterol from peripheral cells.

  • Delivers excess cholesterol esters back to liver via scavenger receptors.

Summary of Lipoproteins and Cardiovascular Disease

  • Role of LDL: Associated with increased cardiovascular disease risk; HDL considered protective.

  • Lifestyle choices impact CVD risk due to ratios of HDL to LDL.

Key Learning Points

  • Understand the mechanics of lipoprotein transport and regulation in the body.

  • Recognize the distinct functions of chylomicrons, VLDLs, IDLs, LDLs, and HDLs.

  • Recognize the role of lipoprotein lipase and cholesterol synthesis pathways in maintaining lipid homeostasis.

Familial Hypercholesterolemia

  • Condition Description: Autosomal dominant genetic disease with mutations affecting LDL receptor pathways, leading to elevated cholesterol and increased cardiovascular risk.

  • Impact: Increased LDL in the blood heightens chances for coronary heart disease (CHD).

Atherosclerosis and LDL Pathology

  • Process involving LDL oxidation, macrophage accumulation, and plaque formation, potentially culminating in cardiovascular events.