Lipoprotein Handling Notes

Lipoproteins Overview

  • Lipoproteins are particles made of proteins and lipids found in plasma.
  • Their main function is to transport hydrophobic lipids like triacylglycerides (TAG/TG) and cholesterol between the liver, intestine, and all body tissues.
  • The amount of transported TAG depends on the body’s energy needs.
  • The cholesterol transported is part of the extracellular pool for cells.
  • Problems with lipoprotein handling can lead to atherosclerosis, cardiovascular disease, stroke, and peripheral vascular disease.

Global Causes of Death

  • Cardiovascular diseases are a leading cause of death globally.
  • Behavioral risk factors such as alcohol and drug use, dietary risks, tobacco smoke, and low physical activity contribute to mortality.
  • Metabolic risk factors including high body mass index, high systolic blood pressure, high total cholesterol, and high fasting plasma glucose also increase mortality.
  • Environmental risk factors like air pollution play a role.

Lipoprotein Composition and Structure

  • Most fatty acids come from the diet in the form of triglycerides (90%), cholesterol, cholesterol esters, phospholipids, or free fatty acids (FA).
  • FA can be synthesized in the liver during excess energy intake.
  • Triglycerides and cholesterols are highly hydrophobic and must be packed in a lipid/protein coat forming lipoproteins for transport in the blood.
  • Lipoproteins have an outer hydrophilic coat composed of:
    • Phospholipids (amphipathic).
    • Free cholesterol (amphipathic).
    • Apoproteins.
  • The inner hydrophobic core contains:
    • Cholesterol.
    • Cholesterol esters.
    • Triglycerides.
    • Some vitamins (A and E).

Classes of Lipoproteins

  • Lipoproteins transport fats and cholesterols between:
    • The gut (digested food) and the rest of the body.
    • The liver and peripheral tissues.
    • Peripheral tissues back to the liver.
  • Major differences between lipoproteins include:
    • Size.
    • Fat/TG and cholesterol content.
    • Different apoproteins, which determine the lipoprotein's fate and interactions and can inhibit/activate certain enzymes.
  • Apolipoproteins are proteins that bind lipids and may be embedded in the surface of the particle or loosely bound and exchanged.

Specific Lipoproteins and Their Roles

  1. Chylomicrons
    • Formed in the gut during digestion.
    • Carry fat/cholesterol from the GI tract to peripheral tissues.
    • Apoproteins include B48, A, C, and E.
  2. VLDL (Very Low-Density Lipoproteins)
    • Formed in the liver from excess energy and remnants from chylomicrons.
    • Distribute triglycerides to peripheral tissues.
    • Apoproteins include B100, A, C, and E.
  3. IDL (Intermediate-Density Lipoproteins)
    • Formed from VLDLs that have had triglycerides partially absorbed by peripheral tissue.
    • Contain apoproteins B100 and E.
  4. LDL (Low-Density Lipoproteins)
    • Represent remnants of VLDL and IDL.
    • Deliver cholesterol to peripheral cells.
    • Contain apoprotein B100.
  5. HDL (High-Density Lipoproteins)
    • Scavengers of cholesterol from peripheral cells.
    • Return excess cholesterol to the liver.
    • Contain apoproteins AI, AII, C, and E.

Lipoprotein Metabolism

  • Chylomicron Metabolism

    • Chylomicrons are formed from fats and cholesterol absorbed from the GI tract and enter the lymphatic system before the blood.
    • In the lymphatic system, chylomicrons interact with HDL, which donates Apo E and C2.
    • ApoC2 enables chylomicrons to give triglycerides to peripheral cells.
    • ApoE allows the chylomicron remnant to be taken up by the liver.

  • VLDL Formation

    • Similar to chylomicron formation, but VLDLs are produced by the liver.
    • Require addition of ApoC2 and ApoE from HDLs.
    • Remnant VLDLs are either re-absorbed by the liver or become LDLs.

Lipoprotein Lipase (LPL)

  • LPL is the main regulator of triglyceride transfer from VLDL and chylomicrons to target cells.
  • Acts as the gatekeeper of lipoprotein metabolism.
  • LPL breaks down triglycerides into free fatty acids that can be taken up by peripheral cells.
  • Apo C2 activates LPL on the luminal surface of capillaries.
  • During starvation:
    • LPL activity is highest in muscle.
  • After a meal:
    • LPL activity is highest in adipose cells.
  • Chylomicrons and VLDLs mainly transfer triglycerides, while LDLs transfer cholesterol.

Low-Density Lipoproteins (LDL)

  • The function of LDL is to deliver cholesterol to peripheral cells.
  • LDLs are formed from VLDLs after triglycerides have been distributed.
  • As VLDLs lose triglycerides, they become denser and form IDLs.
  • IDLs are absorbed by the liver, where hepatic TAG ligase (HTGL) converts IDL to cholesterol-rich LDL with Apo B100.
  • ApoB100 binds to LDL receptors on the surface of target cells, facilitating receptor-mediated endocytosis.

Cholesterol

  • Cholesterol is important for cell membranes, steroid hormone biosynthesis, and bile acid formation.
  • Most cells synthesize cholesterol from acetyl CoA using HMG-CoA reductase.
  • High cholesterol levels trigger negative feedback:
    1. Reduced gene expression of HMGCoA reductase.
    2. Reduced gene expression of LDLR.
    3. Excess cholesterol is stored as cholesterol esters.

High-Density Lipoprotein (HDL)

  • HDL has two important functions:
    • Apoprotein exchange.
    • Reverse cholesterol transport.
  • HDL is produced in the liver as a precursor containing mainly ApoA1 (pre-β HDL).
  • HDL collects cholesterol from other cells via ABCA1/G1 membrane transport proteins and esterifies it to cholesterol ester.
  • HDL transfers excess cholesterol ester to the liver by binding to scavenger receptors (SR-B1) on hepatocytes.
  • The liver eliminates excess cholesterol esters in bile.

Familial Hypercholesterolemia

  • Autosomal dominant genetic disease caused by mutations in:
    1. LDLR (receptor for receptor-mediated endocytosis).
    2. PCSK9 (kinase enzyme that controls the recycling of LDL receptors).
    3. APOB (gene for ApoB 100).
  • Causes high LDL levels, increasing the risk of CHD.
  • Prevalence of 1 in 500 in the UK.
  • Can cause heart attacks even in children with homozygous mutations.

Lipoproteins and CVD

  • High LDL is associated with increased CVD risk, while HDL is considered protective.
  • Lifestyle choices are closely associated with CVD risk.

Apo Proteins and CVD

  • Apoproteins have diagnostic value.
  • APOA (HDL) & APOB (LDL), measured as APOA/APOB ratio, have better diagnostic value than total cholesterol or HDL alone.

Atherosclerosis and Plaque Formation

  • High triglyceride levels and cholesterol are associated with atherosclerosis (narrowing of arteries due to plaque formation).
  • Steps in plaque formation:
    1. LDLs become damaged and oxidized.
    2. Oxidized LDLs bind to scavenger receptors on macrophages and are absorbed.
    3. Macrophages accumulate LDL and become foam cells.
    4. Foam cells accumulate with other immune cells and muscle cells on artery walls, forming fatty streaks that become plaques.

Cardiovascular Risk Factors

  • Male sex (risk equalizes in postmenopausal women).
  • Age.
  • Smoking.
  • Hypertension.
  • High plasma total cholesterol.
  • High plasma LDL cholesterol.
  • Low plasma HDL cholesterol.
  • Diabetes mellitus.
  • Impaired renal function.
  • Family history of premature atherosclerotic CVD.
  • High plasma apoB.
  • Low plasma apoA.
  • Social deprivation.
  • Autoimmune inflammatory conditions.

Foods That Lower/Increase Cholesterol

  • Foods that lower cholesterol: salmon, sweet potatoes, whole grains, nuts, margarine, oatmeal, beans, apples, olives, avocado, orange, Brussels sprouts, berries.
  • Foods that increase cholesterol: microwave popcorn, butter, macaroni & cheese, hamburger, fried chicken, french fries, shellfish, cream cheese, ice cream, egg yolks, red meat.

Statins

  • Statins are a common treatment for high cholesterol or lipids (hyperlipidemia).
  • Statins block HMG-CoA reductase activity by acting as a competitive inhibitor.
  • This reduces endogenous cholesterol production and increases cellular uptake of LDL, thus reducing blood cholesterol levels.