Lipoproteins lacking cholesteryl esters

According to the above developed scheme of HDL and LDL structure, the molecular structure of cholesteryl esters is an important determinant to the size and internal arrangement of lipoproteins. This is further demonstrated by the structures of lipoprotein particles which lack cholesteryl esters. A natural system, where this is the case, is given by the abnormal lipoprotein Lp-X oc-curing abundantly in the serum of patients suffering from obstructive jaundice or from a familial deficiency in the enzyme lecithin-cholesterol-acyltransferase, which controls the conversion of cho-... 

Dedecjus M, Masson D, Gautier T, de Barros JP, Gambert P, Lewinski A, Adamczewski Z, Moulin P, Lagrost L (2003) Low cholesteryl ester transfer protein (CETP) concentration but normal CETP activity in serum from patients with short-term hypothyroidism Lack of relationship to lipoprotein abnormalities. Clin Endocrinol (Oxf) 58 581-588... 

Once lipoprotein cholesterol enters the cell, the cholesteryl esters are hydrolyzed by lysosomal acid lipase. The lack or malfunction of this enzyme results in intracellular accumulation of cholesterol esters and produces a clinical disorder known as cholesteryl ester storage disease. 

Cholesteryl esters are quantitatively minor constituents (5-15% of total lipids) of VLDLs but the amount of cholesteryl esters relative to TG in VLDLs increases when rats are fed a high cholesterol diet. The esterification of cholesterol is mediated by two distinct acyl-CoA cholesterol acyltransferases (ACATs) [11]. Inhibition of cholesterol esterification with an ACAT inhibitor in hepatocytes decreased apo B secretion in some studies but not in others. For example, severe reduction in cholesteryl ester content of hepatoma cells decreased apo B secretion, whereas increased cholesteryl ester content did not stimulate apo B secretion. In mouse liver and intestine, the majority of cholesteryl esters are made by ACAT2. Nevertheless, normal quantities of apo B-containing lipoproteins are produced in mice lacking ACAT2 despite the absence of essentially all hepatic ACAT activity. However, ACAT2-deficient mice exhibit reduced intestinal absorption of cholesterol and are resistant to diet-induced hypercholesterolemia (R.V. Farese, 2(X)0). Thus, the observed reduction of plasma cholesterol in response to ACAT inhibitors is probably due to decreased cholesterol absorption rather than decreased VLDL secretion. 

C-II, the activator of lipoprotein lipase, may be sequestered on LP-X. Thus, production of HDL by lipolytic processes may be severely hampered. Lack of C-III, also due to loss to LP-X, may lead to a rapid catabolism of triglyceride-rich lipoproteins and thus cause a deprivation of the substrate for HDL formation. Lack of C-III may also increase catabolism of HDL particles. Absence of acceptors for Apo-E (TG-rich lipoproteins) from HDL may increase catabolism of HDL particles via B E- or renmant receptors. Impaired hepatic lipase may lead to abnormal particles with a short life-span. This may be also due to a disturbed exchange of cholesteryl esters and triglycerides. 

Wu, X., Sakata, N., Lui, E., and Ginsberg, H.N., 1994. Evidence for a lack of regulation of the assembly and secretion of apolipoprotein B-containing lipoprotein from HepG2 cells by cholesteryl ester. The Journal of Biological Chemistry. 269 12375-12382. 

An inherited lack of, or deficiency in, cell surface receptors for low density lipoproteins results in a condition, familial hypercholesterolaemia, in which blood cholesterol concentrations are rather high. This condition, if untreated, leads to severe vascular disease and death from ischaemic heart disease. Lipids are involved in several ways. First, one of the characteristics of developing atherosclerotic plaques is an accumulation of lipids, particularly cholesteryl esters, which are derived from plasma lipoproteins secondly, lipids are involved (because of their role as precursors of eicosanoids) in the formation of thrombi which may block arteries and cause ischaemia. Another risk factor for ischaemic heart disease that involves lipid metabolism is obesity, characterized by an excessive accumulation of adipose tissue. In particular, upper body obesity is also associated with Type II diabetes and hyperinsulinaemia. Hyperlipoproteinaemia is secondary to obesity and diabetes mellitus and if these conditions are treated, blood lipid concentrations return to normal. 

---