Lipoprotein Metabolism 6iz73

LIPOPROTEIN METABOLISM

Prepared by

Darien Liew Daojuin 13 August 2017

CONTENTS 1.

Lipids

2.

Lipoproteins

3.

Apolipoproteins

4.

Fat metabolism exogenous – intestinal absorption endogenous

reverse cholesterol transport 1.

Association with atherosclerosis

2.

Summary

LIPIDS It comprises a group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E, and K), monoglycerides, diglycerides, triglycerides, phospholipids, and others.

NORMAL LIPID VALUES

LIPOPOROTEINS INTRODUCTION

Large macromolecular complexes composed of lipids and proteins that transport poorly soluble lipids (primarily triglycerides, cholesterol, and fat-soluble vitamins) through body fluids (plasma, interstitial fluid, and lymph) to and from tissues. Play an essential role in the  absorption of dietary cholesterol, long chain fatty acids, and fat-soluble vitamins  the transport of triglycerides, cholesterol, and fat-soluble vitamins from the liver to peripheral tissues  the transport of cholesterol from peripheral tissues to the liver and intestine.

What is apolipoproteins? These are proteins associated with lipoprotein.

LIPOPROTEINS CLASSIFICATION

Function? Involved in assembly, structure, function, and metabolism of lipoproteins. Activate enzymes important in lipoprotein metabolism and act as ligands for cell surface receptors.

A breakdown of VLDL will form IDL

APOLIPOPROTEINS Apolipoproteins are proteins that bind lipids to form lipoproteins.

They facilitate lipoproteins to transport lipids through the lymphatic and circulatory systems

APOLIPOPROTEINS Because lipids are insoluble, apolipoproteins have detergent like (amphipathic) properties, alongside phospholipids, can surround lipids, creating a lipoprotein particle that is water soluble and can move through the blood circulatory system.

Apolipoproteins also serve as enzyme cofactors, receptor ligands and lipid transfer carriers that regulate the metabolism of lipoproteins and their uptake in tissues.

APOLIPOPROTEINS

ENZYMES IN LIPID METABOLISM

FAT METABOLISM 1.

Exogenous

2.

Endogenous

3.

Reverse cholesterol transport

Luminal Phase

Fat Solubilisation

Lipase Action

Absorption Exocytosis

1. Exogenous source of lipid via intestinal absorption. 2. From the lacteals to the blood stream, chylomicrons are modified by apolipoproteins and hydrolysed by LPL on the endothelium. 3. LDL remnants are rapidly cleared in the liver by binding to LDL receptos. 4. Secretion of VLDL by the liver, rich in TG. Differ from chylomicrons due to full length Apo-B. 5. VLDL gets hydrolysed to release TG which can form FFA. This converts VLDL to IDL, and cleared by the liver, by LDLR. 6. Some IDL gets converted to LDL, by removing the TG and other materials, except Apo B100.

In dyslipoproteinamia conditions, when there is a defective LDLR (familial hypercholesterolemia), LDL accumulates in the blood and is subjected to oxidation.

In hyperlipidemia, it can cause endothelial injury, lipoproteins accumulate within the intima, and generate oxidised LDL and cholesterol crystals. In addition, Apo B (in the LDL) that can no longer be cleared, triggers inflammation  foam cells.

More LDLs come by, coupled with smooth muscle recruitment, proliferation and deposition of collagen, ECM and lipid, this results in atherosclerosis.

ASSOCIATION BETWEEN HYPERLIPIDEMIA, ENDOTHELIAL DYSFUNCTION AND ATHEROSCLEROSIS

Defective LDL Receptors Hyperlipidemia

Atherosclerosis

REVERSE CHOLESTEROL TRANSPORT 1. Lipid poor Apo A1, from the liver and immature HDL accepts cellular cholesterol and phospholipids via ABCA1. 2. This produces HDL (contains cholesterol) which can take in more cholesterol from the cells, via ABCG1. 3. Small HDL gets esterified by LCAT, to maintain an uptake gradiet and mature the HDL..

LOW DENSITY LIPOPROTEINS LDL particles contain cholesterol, triglycerides, phospholipids, and apolipoproteins B-100 and C-III. Elevated plasma concentrations of apo B-100-containing lipoproteins can induce the development of atherosclerosis even in the absence of other risk factors. It has been proposed that the initiating event in atherogenesis is the subendothelial retention of apo B-100-containing lipoproteins via a charge-mediated interaction with proteoglycans in the extracellular matrix.

HIGH DENSITY LIPOPROTEIN HDL particles, in contrast to LDL and VLDL particles, have antiatherogenic properties that include     

removal of cholesterol from macrophages (termed macrophage cholesterol efflux), antioxidation, protection against thrombosis, maintenance of endothelial function, and maintenance of low blood viscosity through an action on red cell deformability

So what about triglycerides?

TRIGLYCERIDES Triglycerides role in atherosclerosis is likely because of  delayed clearance of triglyceride-rich lipoproteins on VLDL particles that carry apo CIII or reduced lipoprotein lipase activity, which is common in insulin resistance,  the VLDL remnants may enter the vessel wall or be converted to small LDL particles.  Small LDL particles have conformational changes in apoB – reduced LDL receptormediated clearance – allowing these particles to circulate for a longer duration where they become susceptible to oxidation, glycation, and glyco-oxidation.

Further Reading

Further Reading

CETP High concentrations of chylomicron remnants or VLDL particles result in lower levels of HDL cholesterol, due to cholesterol ester transfer protein (CETP) – mediating a process of exchange HDL/LDL to VLDL/chylomicrons. Triglyceride-enriched HDL particles have reduced macrophage cholesterol efflux capacity. Triglyceride-rich lipoproteins increase endothelial activation, facilitate monocyte infiltration into the arterial wall, and increase activation of proinflammatory genes via AP-1

TG

HDL

Cholesterol Estyl

Phospholipids

VLDL

SUMMARY

REFERENCES UpToDate  https://www-uptodate-com.ezproxy.lib.monash.edu.au/contents/lipoproteinclassification-metabolism-and-role-inatherosclerosis?source=see_link&sectionName=LIPOPROTEINS%20AND%20ATHERO SCLEROSIS&anchor=H15#H16

Medscape  http://www.medscape.org/viewarticle/416521_2

Davidson’s Principles and Practice of Medicine, 22nd Edition Robbin’s Basic Pathology, 9th Edition