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Protective effects of farnesoid X receptor (FXR) on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal


Schmitt, Johannes; Kong, Bo; Stieger, Bruno; Tschopp, Oliver; Schultze, Simon M; Rau, Monika; Weber, Achim; Muellhaupt, Beat; Guo, Grace L; Geier, Andreas (2015). Protective effects of farnesoid X receptor (FXR) on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal. Liver International, 35(4):1133-1144.

Abstract

Background & Aims
There is a growing evidence that bile acids are involved in the regulation of triglyceride-, cholesterol-homoeostasis and fat absorption. In this study organ-specific Fxr knockout mice were used to further investigate the influence of farnesoid X receptor FXR in lipogenesis.
Methods
Liver- and intestine-specific Fxr knockout mice were fed a 1% cholesterol diet for 28 days. Histological examination of frozen tissue sections included Sudan III/H&E, BODIPY staining and liver X receptor (LXR) immunohistochemistry. Liver triglycerides, serum cholesterol, serum bile acids and nuclear LXR protein were measured. mRNA expression of several genes involved in bile acid-, cholesterol-homoeostasis and lipogenesis was quantified by real-time PCR.
Results
Hepatic FXR deficiency contributes to lipid accumulation under 1% cholesterol administration which is not observed in intestinal Fxr knockout mice. Strong lipid accumulation, characterized by larger vacuoles could be observed in hepatic Fxr knockout sections, while intestinal Fxr knockout mice show no histological difference to controls. In addition, these mice have the ability to maintain normal serum cholesterol and bile acid levels. Hepatic Fxr knockouts were characterized by elevated triglycerides and bile acid levels. Expression level of LXR was significantly elevated under control and 1% cholesterol diet in hepatic Fxr knockout mice and was followed by concomitant lipogenic target gene induction such as Fas and Scd-1. This protective FXR effect against hepatic lipid accumulation was independent of intestinal Fgf15 induction.
Conclusion
These results show that the principal site of protective bile acid signalling against lipid accumulation is located in the liver since the absence of hepatic but not intestinal FXR contributes to lipid accumulation under cholesterol diet.

Abstract

Background & Aims
There is a growing evidence that bile acids are involved in the regulation of triglyceride-, cholesterol-homoeostasis and fat absorption. In this study organ-specific Fxr knockout mice were used to further investigate the influence of farnesoid X receptor FXR in lipogenesis.
Methods
Liver- and intestine-specific Fxr knockout mice were fed a 1% cholesterol diet for 28 days. Histological examination of frozen tissue sections included Sudan III/H&E, BODIPY staining and liver X receptor (LXR) immunohistochemistry. Liver triglycerides, serum cholesterol, serum bile acids and nuclear LXR protein were measured. mRNA expression of several genes involved in bile acid-, cholesterol-homoeostasis and lipogenesis was quantified by real-time PCR.
Results
Hepatic FXR deficiency contributes to lipid accumulation under 1% cholesterol administration which is not observed in intestinal Fxr knockout mice. Strong lipid accumulation, characterized by larger vacuoles could be observed in hepatic Fxr knockout sections, while intestinal Fxr knockout mice show no histological difference to controls. In addition, these mice have the ability to maintain normal serum cholesterol and bile acid levels. Hepatic Fxr knockouts were characterized by elevated triglycerides and bile acid levels. Expression level of LXR was significantly elevated under control and 1% cholesterol diet in hepatic Fxr knockout mice and was followed by concomitant lipogenic target gene induction such as Fas and Scd-1. This protective FXR effect against hepatic lipid accumulation was independent of intestinal Fgf15 induction.
Conclusion
These results show that the principal site of protective bile acid signalling against lipid accumulation is located in the liver since the absence of hepatic but not intestinal FXR contributes to lipid accumulation under cholesterol diet.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Gastroenterology and Hepatology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Endocrinology and Diabetology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2015
Deposited On:12 Feb 2014 09:59
Last Modified:05 Apr 2016 17:37
Publisher:Wiley-Blackwell
ISSN:1478-3223
Publisher DOI:https://doi.org/10.1111/liv.12456
PubMed ID:25156247

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