Differential regulation of bile acid and cholesterol metabolism by the farnesoid X receptor in Ldlr −/− mice versus hamsters

Gardès, Christophe; Chaput, Evelyne; Staempfli, Andreas; Blum, Denise; Richter, Hans G.; Benson, G. Martin

doi:10.1194/jlr.m033423

Cited by 32 publications

(29 citation statements)

References 70 publications

(78 reference statements)

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“…In the previous report of HFD-fed hamsters, OCA reduced liver BA pool size and fecal BAs (22), which was in line with our current study of HFHCD-fed hamsters in which OCA treatment of 14 days reduced fecal BAs by 62%. Importantly, in addition to reduction of fecal BAs, the current study demonstrated a reduction of hepatic cholesterol contents and an increase in fecal cholesterol levels in OCAtreated hamsters.…”

Section: Lxr Activation Alone Did Not Induce Hepatic Expression Of Srsupporting

confidence: 80%

“…**P < 0.01 as compared with the control group. treatment of 11 days at a daily dose of 30 mg/kg reduced cumulative food intake by 13%, lowered HDL-C, and increased VLDL-C, resulting in unchanged total plasma cholesterol levels (22,24). In our study, we observed a similar amount of reduction in cumulative food intake (14%), but we observed significant HDL-C reduction without any elevation of VLDL-C or LDL-C.…”

Section: Lxr Activation Alone Did Not Induce Hepatic Expression Of Srsupporting

confidence: 64%

“…In another study conducted in wildtype C57BL/6J mice fed a high-fat diet (HFD), OCA showed no effect on plasma TC level or LDL-C levels, but caused a small increase in HDL-C (23). In contrast to the lack of effect in reduction of plasma HDL-C in mice, administration of OCA to golden Syrian hamsters fed a HFD led to a reduction of HDL-C and a small increase in VLDL-cholesterol (VLDL-C), while total plasma cholesterol levels were unchanged (22,24). Interestingly, despite the inconsistent changes on plasma HDL-C metabolism in these animal models after OCA treatment, OCA-modulated expression of typical FXR-regulated genes involved in the BA synthetic pathway, including CYP7Α1 and SHP, were consistently demonstrated in all those studies.…”

Section: Hplc Separation Of Serum Lipoprotein Cholesterol and Tgsmentioning

confidence: 83%

“…In Zucker (fa/fa) obese rats fed a normal chow diet (NCD), OCA effectively lowered plasma HDL-C and TG levels, which were accompanied by reduced expression of hepatic lipogenic genes (21). In LDL receptor (LDLR) / mice, OCA treatment did not alter plasma TC levels or plasma lipoprotein profile (22). In another study conducted in wildtype C57BL/6J mice fed a high-fat diet (HFD), OCA showed no effect on plasma TC level or LDL-C levels, but caused a small increase in HDL-C (23).…”

Section: Hplc Separation Of Serum Lipoprotein Cholesterol and Tgsmentioning

confidence: 99%

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Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters

Dong

Young

Liu

et al. 2017

Journal of Lipid Research

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Section: Lxr Activation Alone Did Not Induce Hepatic Expression Of Srsupporting

confidence: 80%

Section: Lxr Activation Alone Did Not Induce Hepatic Expression Of Srsupporting

confidence: 64%

Section: Hplc Separation Of Serum Lipoprotein Cholesterol and Tgsmentioning

confidence: 83%

Section: Hplc Separation Of Serum Lipoprotein Cholesterol and Tgsmentioning

confidence: 99%

See 2 more Smart Citations

Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters

Dong

Young

Liu

et al. 2017

Journal of Lipid Research

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“…The results of this study demonstrate in vivo in patients and transgenic mice as well as in vitro in hepatocytes and macrophages that human CETP is positively regulated by to FXR activation ( 46 ), which represents a signifi cant contributing factor to total cholesterol levels in mice on a Western-type diet. In contrast, the mice in our study were fed chow and subsequently showed an increase in VLDL/ LDL cholesterol as a refl ection of increased CETP activity.…”

Section: Discussionmentioning

confidence: 89%

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

Gautier

Haan

Grober

et al. 2013

Journal of Lipid Research

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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

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Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice

Zalzala

et al. 2016

Hepatology

135

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Activation of farnesoid X receptor (FXR) markedly attenuates the development of atherosclerosis in animal models. However, the underlying mechanism is not well elucidated. Here we show that the FXR agonist obeticholic acid (OCA) increases fecal cholesterol excretion and macrophage reverse cholesterol transport (RCT) dependent on activation of hepatic FXR. OCA does not increase biliary cholesterol secretion but inhibits intestinal cholesterol absorption. OCA markedly inhibits hepatic cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1) partly through inducing small heterodimer partner (Shp), leading to reduced bile acid pool size and altered bile acid composition, with the α/β-muricholic acid proportion in the bile increased by 2.6 fold and taurocholic acid (TCA) level reduced by 71%. Over-expression of Cyp8b1 or concurrent over-expression of Cyp7a1 and Cyp8b1 normalizes TCA level, bile acid composition and intestinal cholesterol absorption. Conclusions Our data indicate that activation of FXR inhibits intestinal cholesterol absorption via modulation of bile acid pool size and composition, thus leading to increased RCT. Targeting hepatic FXR and/or bile acids may be useful for boosting RCT and preventing the development of atherosclerosis.

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Differential regulation of bile acid and cholesterol metabolism by the farnesoid X receptor in Ldlr −/− mice versus hamsters

Cited by 32 publications

References 70 publications

Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters

Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters

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

Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice

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