Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice

Abstract

The cholesteryl ester transfer protein (CETP) promotes the heteroexchange of cholesteryl esters and triglycerides (TG) between plasma high density lipoproteins (HDL) and apoB-containing lipoproteins, resulting in a proatherogenic plasma lipid profi le with increased VLDL and LDL cholesterol levels and decreased HDL cholesterol (HDL-C) ( 1, 2 ). Given the key importance of dyslipidemia for the development of atherosclerosis ( 3 ), most ( 1, 2, 4-6 ) but Abstract Cholesteryl ester transfer protein (CETP) activity results in a proatherogenic lipoprotein profi le. In cholestatic conditions, farnesoid X receptor (FXR) signaling by bile acids (BA) is activated and plasma HDL cholesterol (HDL-C) levels are low. This study tested the hypothesis that FXR-mediated induction of CETP contributes to this phenotype. Patients with cholestasis and high plasma BA had lower HDL-C levels and higher plasma CETP activity and mass compared with matched controls with low plasma BA (each P < 0.01). BA feeding in APOE3*Leiden transgenic mice expressing the human CETP transgene controlled by its endogenous promoter increased cholesterol within apoBcontaining lipoproteins and decreased HDL-C (each P < 0.01), while hepatic CETP mRNA expression and plasma CETP activity and mass increased (each P < 0.01). In vitro studies confi rmed that FXR agonists substantially augmented CETP mRNA expression in hepatocytes and macrophages dependent on functional FXR expression (each P < 0.001). These transcriptional effects are likely mediated by an ER8 FXR response element (FXRE) in the fi rst intron. In conclusion, using a translational approach, this study identifi es CETP as novel FXR target gene. By increasing CETP expression, FXR activation leads to a proatherogenic

Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II

“…For instance, treatment of CETPtg mice with CETP antisense oligonucleotide or CETP inhibitor, anacetrapib, increased serum HDL-cholesterol levels, whereas results were slightly increased or had no effect on serum TG levels (36). In APOE*3-Leiden.CETP transgenic mice, activation of farnesoid X receptor by taurocholic acid increased CETP expression, which was associated with decreased HDL-C and TG levels in serum (37). Similarly, we determined that Topo II inhibitor decreased both serum HDL-C and TG levels in CETPtg mice in our study.…”

Lipopolysaccharide Lowers Cholesteryl Ester Transfer Protein by Activating F4/80 + Clec4f + Vsig4 + Ly6C − Kupffer Cell Subsets

“…36 Although it cannot be excluded that some regulatory elements may be missing from this construct, this human CETP transgenic mice were shown to respond in a human-like fashion to LXR agonism 37 and FXR agonism. 46 Notably, in E3L.CETP mice, the markedly increased HDL-C/ non-HDL-C ratio was already normalized at 48 hours after LPS injection, whereas plasma CETP level and hepatic CETP mRNA expression were still lower at this time point. Moreover, in healthy subjects, 24 hours after LPS injection, they had decreased plasma TG 21 and CETP concentration as shown in the present study, while plasma HDL-C was not changed.…”

CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients

“…Farnesoid X receptor activation affects bile acid production, hepatic lipogenesis, cholesterol synthesis and glucose homoeostasis and protects hepatocytes against bile acid‐induced cytotoxicity . Evidence from animal models suggests that FXR activation may lead to increases in LDLc concentrations and decreases in HDLc concentrations . Clinical evidence, based on OCA administration, indicates the same effects are observed in humans; additional studies using other FXR agonists are underway …”