Very lowdensity lipoproteins VLDL and lowdensity lipoproteins LDL

VLDL are assembled in the liver, and contain newly synthesized triacylglycerol, cholesterol and cholesteryl esters and phospholipids as well as lipids from chylomicron remnants. These lipids are taken up by peripheral tissues which have cell-surface lipoprotein lipase, phospholipase and cholesterol esterase.

As the VLDL particles are progressively depleted of lipids, they transfer apoproteins C-I and C-II to HDL, forming intermediate-density lipoprotein particles (IDL). IDL take up cholesteryl esters from HDL, becoming LDL.

LDL are cleared from the circulation by receptor-mediated uptake in the liver. Both the receptor and the LDL are internalized; the LDL is hydrolysed in lysosomes by proteases and lipases, and the receptor is recycled back to the cell surface.

Cholesterol represses synthesis of the LDL receptor, so that when there is an adequate amount of cholesterol in the liver less LDL will be cleared. The hypocholesterolaemic statin drugs both inhibit cholesterol synthesis and also increase clearance of LDL, because there is now less repression of receptor synthesis.

As discussed in section 7.2, elevated LDL cholesterol is one of the major factors in the development of atherosclerosis and ischaemic heart disease. Two factors are involved in elevated LDL cholesterol:

  • Increased synthesis and secretion of VLDL — this in turn will be a consequence of a high fat intake, as there is more lipid from chylomicron remnants to be exported from the liver in VLDL.
  • Decreased clearance of LDL by receptor-mediated uptake into the liver. This may be due to:
  • Low levels of LDL receptor synthesis (especially when hepatic cholesterol levels are high, but also genetically determined in some of the familial hyperlipidaemias).
  • Poor affinity of some genetic variants of apoprotein E for the LDL receptor. This is the basis of some genetic susceptibility to atherosclerosis.
  • Chemical modification of apoprotein E in the circulation, so reducing its affinity for the hepatic receptors. Commonly, this is secondary to oxidative damage to unsaturated fatty acids in LDL — hence the role of antioxidants in reducing the risk of atherosclerosis (section 7.4.3). High levels of homocysteine (section can also lead to modification of apoprotein E.

LDL that are not cleared by the liver are taken up by the macrophage scavenger receptor; unlike hepatic uptake, this is an unregulated process, and macrophages can take up an almost unlimited amount of lipid from LDL. Lipid-engorged macrophages (foam cells) infiltrate blood vessel endothelium, forming fatty streaks that eventually develop into atherosclerotic plaque.

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