Protective effects of farnesoid X receptor (FXR) on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal. (7th February 2014)

• Record Type: Journal Article
• Authors: Schmitt, Johannes; Kong, Bo; Stieger, Bruno; Tschopp, Oliver; Schultze, Simon M.; Rau, Monika; Weber, Achim; Müllhaupt, Beat; Guo, Grace L.; Geier, Andreas
• Is Part Of: Liver international. Volume 35:Number 4(2015:Apr.)
• Page Start: 1133
• Page End: 1144
• Publication Date: 2014-02-07
• Subjects: Liver -- Periodicals; Liver -- Diseases -- Periodicals; 616.362
• DOI: 10.1111/liv.12456
• Languages: English
• ISSNs: 1478-3223

Abstract

<abstract abstract-type="main" id="liv12456-abs-0001"> <title>Abstract</title> <sec id="liv12456-sec-0001" sec-type="section"> <title>Background & Aims</title> <p>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.</p> </sec> <sec id="liv12456-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="liv12456-sec-0003" sec-type="section"> <title>Results</title> <p>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 <italic>Fxr</italic> knockout sections, while intestinal <italic>Fxr</italic> 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 <italic>Fxr</italic> 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 <italic>Fxr</italic> 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.</p> </sec> <sec id="liv12456-sec-0004" sec-type="section"> <title>Conclusion</title> <p>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.</p> </sec> </abstract>