Metabolism and Modification of Apolipoprotein B-Containing Lipoproteins Involved in Dyslipidemia and Atherosclerosis

Abstract

Increased levels of apolipoprotein B (apoB)-containing lipoproteins, such as low density lipoproteins (LDL) and chylomicron remnants, are associated with the development of atherosclerosis. Chylomicrons containing apoB-48 are secreted from the intestine during the postprandial state, whereas very low density lipoproteins (VLDL) containing apoB-100 are constitutively formed in the liver. Chylomicron remnants and VLDL remnants are produced by the lipoprotein lipase-mediated lipolysis of triglycerides, which is activated by apolipoprotein C-II bound on the particle surfaces. The hepatic uptake of these remnants is facilitated by apolipoprotein E (apoE), but is inhibited by apolipoproteins C-I, C-II and C-III. In the plasma, VLDL remnants are further converted into LDL by the hydrolysis of triglycerides. ApoB-100 is responsible for the hepatic uptake of LDL. LDL receptor, LDL receptor-related protein and heparan sulfate proteoglycans are involved in the hepatic clearance of lipoproteins containing apoB-100 and/or apoE. The subendothelial retention and modification of apoB-containing lipoproteins are crucial events in the initiation of atherosclerosis. In the subendothelium, the uptake of modified lipoproteins by macrophages leads to the formation of foam cells storing excess amounts of cholesteryl esters and subsequently to apoptosis. This review describes the current knowledge about the metabolism and modification of apoB-containing lipoproteins involved in dyslipidemia and atherogenesis. In particular, I focus on the effects of apolipoproteins, lipid composition and particle size on lipoprotein metabolism and on the roles of cholesterol, sphingomyelinase and apoB denaturation in macrophage foam cell formation and apoptosis. A detailed understanding of these mechanisms will help to develop new therapeutic strategies.

Untitled

“…Oxidation of lipoproteins involves the attack on many constituents, including cholesterol, fatty acids, antioxidants 9 . The presence of small dense LDL with persistent hyperglycemia increases susceptibility of LDL to undergo glycation.…”

Untitled

“…These lipoprotein particles are composed of phospholipids, free cholesterol, triglycerides, cholesterol esters, and apolipoprotein molecules 14 . Oxidation of lipoproteins involves the attack on many constituents, including cholesterol, fatty acids, antioxidants and apoB 16 .…”

“…Lp(a), another lipoprotein, is a form of LDL that is modified in the liver by covalent attachment of apoB to apoA-1 16 . In addition, LDL and Lp(a) are retained in the arterial intima and is modified by the intimal enzymes and agents.…”

“…Lp(a) is rich in potentially atherogenic oxidized phospholipids. Lp(a) also has antifibrinolytic effects, which enhance its atherogenicity 16 . Although its importance in lesion development, our results don't show significant difference in Lp(a).…”

“…This can be explained by the fact that majority of the study patients has been receiving lipid-lowering agents. It has been shown that LDL-lowering drugs are the most effective therapy against atherothrombotic cardiovascular disease and decrease the probability that apoB-containing lipoproteins will be retained in the subendothelium 16 .…”