Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression

Abstract

In addition to efficiently decreasing VLDLtriglycerides (TGs), fenofibrate increases HDL-cholesterol levels in humans. We investigated whether the fenofibrateinduced increase in HDL-cholesterol is dependent on the expression of the cholesteryl ester transfer protein (CETP). To this end, APOE*3-Leiden (E3L) transgenic mice without and with the human CETP transgene, under the control of its natural regulatory flanking regions, were fed a Westerntype diet with or without fenofibrate. Fenofibrate (0.04% in the diet) decreased plasma TG in E3L and E3L.CETP mice (259% and 260%; P , 0.001), caused by a strong reduction in VLDL. Whereas fenofibrate did not affect HDL-cholesterol in E3L mice, fenofibrate dose-dependently increased HDL-cholesterol in E3L.CETP mice (up to 191%). Fenofibrate did not affect the turnover of HDLcholesteryl ester (CE), indicating that fenofibrate causes a higher steady-state HDL-cholesterol level without altering the HDL-cholesterol flux through plasma. Analysis of the hepatic gene expression profile showed that fenofibrate did not differentially affect the main players in HDL metabolism in E3L.CETP mice compared with E3L mice. However, in E3L.CETP mice, fenofibrate reduced hepatic CETP mRNA (272%; P , 0.01) as well as the CE transfer activity in plasma (273%; P , 0.01). We conclude that fenofibrate increases HDL-cholesterol by reducing the CETPdependent transfer of cholesterol from HDL to (V)LDL, as related to lower hepatic CETP expression and a reduced plasma (V)LDL pool.-van der Hoogt, C. C., W.

PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE

“…However, APOE*3Leiden mice (like WT mice) do not possess a CETP gene, and therefore these mice do not respond to HDL-modulating interventions. By crossbreeding the APOE*3Leiden mice to mice expressing the human CETP gene ( 75 ), APOE*3Leiden.CETP mice were obtained that respond to both lipid-lowering as well as HDL-raising interventions (50)(51)(52)(53)76 ). In the current study, we found signifi cant lowering effects of anti-PCSK9 antibodies on TC and TG levels in APOE*3Leiden.CETP mice, but HDL-C was not affected (data not shown).…”

“…The APOE*3Leiden.CETP mice are a well-established mouse model for familial dysbetalipoproteinemia with human-like lipoprotein metabolism and atherosclerosis development, which respond in a human-like manner to both lipid lowering as well as HDLraising drugs (like statins, fi brates, niacin, etc.) used in the treatment of CVD (49)(50)(51)(52).…”

Salsalate Activates Brown Adipose Tissue in Mice

“…Mice, Diet, and Salsalate Treatment E3L.CETP mice were obtained as previously described (7)(8)(9). To assess the effect of salsalate on progression of obesity, dyslipidemia, and hyperglycemia, 10-week-old male E3L.CETP mice were randomized to receive an HFD (45% kcal lard fat; Research Diets) without or with 0.5% (weight for weight [w/w]) salsalate (2-carboxyphenyl salicylate; TCI Europe N.V.) for 12 weeks.…”

“…The objective of the current study was to investigate the mechanisms underlying the beneficial effects of salsalate on lipid and glucose metabolism by treating APOE*3-Leiden.CETP (E3L.CETP) transgenic mice, a wellestablished model for human-like lipoprotein metabolism (7)(8)(9), with salsalate mixed through the high-fat diet (HFD). We found that salsalate both prevented and reduced HFD-induced weight gain by lowering fat mass accumulation, and improved glucose and lipid metabolism.…”

Effects of Established Hypolipidemic Drugs on HDL Concentration, Subclass Distribution, and Function

“…HDL-C raises results from the increased expression of apoA-II and, at a much lesser extent, apoA-I (Yetukuri et al 2011), as well as to the enhanced cholesterol efflux via the induction of ABCA1 in the liver (Berger et al 2005). In addition, animal studies have shown that fenofibrate reduces CETP hepatic expression (van der Hoogt et al 2007). …”