Decreased cholesteryl ester transfer protein (CETP) mRNA and protein and increased high density lipoprotein following lipopolysaccharide administration in human CETP transgenic mice.

Abstract

IntroductionThe plasma cholesteryl ester transfer protein (CETP) mediates the exchange of HDL cholesteryl esters (CE) The metabolism of HDL is regulated, in part, by the activities of lipases and lipid transfer proteins (1). Cholesteryl esters, generated in HDL by lecithin:cholesterol acyltransferase, are exchanged with triglycerides of VLDL, as a result of the activity of cholesteryl ester transfer protein (CETP)'. The subsequent activity of hepatic lipase on triglyceride-enriched HDL results in a decrease in HDL size and catabolism of the major apoliprotein of HDL, apoA-I (2). In a striking demonstration of the interaction of hypertriglyceridemia with cholesteryl ester transfer processes, hypertriglyceridemic apoC-II transgenic mice show profound reductions in HDL cholesterol and apoA-I when crossed with human CETP/apoA-I transgenic mice, to produce apoA-I/CETP/apoC-llH transgenic mice (3). In addition to plasma triglyceride concentration, effective plasma CETP activity is also influenced by changes in CETP concentration, such as those resulting from changes in dietary cholesterol or probucol therapy (4, 5).HDL is thought to mediate the reverse transport of cholesterol from peripheral tissues to the liver (6). In addition to this well-known role, Ulevitch et al. (7) have suggested another, novel function for HDL, namely to bind bacterial lipopolysaccharide (endotoxin) and thereby to modulate its biological effects. The binding of endotoxin to HDL can prevent endotoxininduced death (8). Harris et al. (9) have shown that VLDL and chylomicrons can also bind endotoxin, and protect mice against endotoxin-induced death. However, the potency of HDL appeared to be greater than that of other lipoproteins (9), and the molar concentrations of HDL in plasma are usually higher than other lipoproteins. Another role of HDL may be to provide cholesterol for adrenal corticosteroid synthesis ( 10-12), a function that could be particularly important during stress (13).The purpose of the present study was to examine the possible regulation of CETP gene expression in response to LPS administration. We suspected that CETP might be altered by LPS, since LPS has profound effects on lipoprotein metabolism and is known to regulate lipoprotein lipase and LCAT activities ( 14,15

Endotoxin and cytokines decrease serum levels and extra hepatic protein and mRNA levels of cholesteryl ester transfer protein in syrian hamsters.

“…The effects of endotoxin on serum levels of CETP in the present study are consistent with the reported results of Masucci-Magoulas et al (19), who demonstrated that endotoxin reduces plasma CETP levels and hepatic mRNA levels for CETP in mice overexpressing the human CETP gene. However, there are significant differences in the results from the two studies.…”

“…hepatic mRNA levels for CETP (19). It was therefore of interest to test whether corticosteroids would mimic the effects of endotoxin on CETP levels in hamsters, where regulation of the native gene can be studied and where serum levels of CETP are likely to be derived from extra hepatic sources.…”

“…In these mice, endotoxin decreases mRNA levels for CETP in the liver and CETP protein in plasma (19). However, endotoxin increased the mRNA levels for CETP in peripheral tissues in the transgenic mice.…”

Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice

“…To that end, a preclinical in vivo experiment was conducted using wild-type (WT) mice (lacking human CETP) and CETP transgenic mice (expressing human CETP transgene) that were fed either a normal or a high-fat diet to increase adiposity. Mice bearing the CETP transgene of the natural flanking region (NFR) have been well characterized (Masucci-Magoulas et al, 1995). Furthermore, diet-induced obese (DIO) mice (fed on high-fat diet for 2 months) have previously been described as animal models to investigate the impact of adiposity on animal physiology (for a representative example, see Li et al, 2010).…”

Cholesteryl ester transfer protein: The controversial relation to atherosclerosis and emerging new biological roles

“…Thus, the authors concluded that CETP is an endogenous component involved in the first line of defense against an exacerbated production of proinflammatory mediators (59). LPS has been previously reported as an inhibitor of CETP mRNA and plasma activity (60,61). Because HDL is known to modulate the acute inflammatory response through the binding and neutralization of bacterial toxins, these results were viewed as an adaptive response during infection and inflammation that helps to maintain an elevated HDL plasma concentration.…”