Protective effects of FXR on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal

Aims: NALFD represents a chronic liver disease and cofactor in other metabolic diseases with worldwide growing incidence. There is growing evidence confirming a functional interaction between FXR-pathways and hepatic triglyceride metabolism. Methods: Liver- and intestine- specific Fxr knockout mice were under 1% cholesterol diet for 28 days. Histological examination of frozen tissue sections included Sudan III/H&E and BODIPY staining. Liver triglycerides, serum cholesterol and serum bile acids were measured. mRNA expression of several genes involved in bile acid homeostasis (Fxr, Shp, Ntcp, Bsep, Cyp7a1 Fgf15), cholesterol homeostasis (Lxr, HmgCoAR, Abcg5, Abcg8) and lipogenesis (Fas, Scd-1, Pnpla3) was quantified by real-time PCR. Results: Our data confirm a protective FXR effect against lipid accumulation in the liver. Deficiency of hepatic FXR contributes to lipid accumulation under 1% cholesterol diet which is not observed in intestinal Fxr knockout mice. Prominent lipid accumulation, characterized by larger vacuoles could be observed in hepatic Fxr knockout sections, while intestinal Fxr were histologically undistinguishable from control mice. Intestinal Fxr knockout mice show the ability to maintain normal serum cholesterol and bile acid levels under 1% cholesterol diet while hepatic Fxr knockout are characterized by elevated triglycerides and bile acid levels. LXR expression of hepatic Fxr knockout mice was significantly elevated under control and 1% cholesterol diet, followed by concomitant lipogenic target gene induction such as Fas and Scd-1. Of note, the protective FXR effect against hepatic lipid accumulation under these conditions was independent of intestinal Fgf15 induction. Conclusions: Our results show that hepatic FXR activation has a protective effect against lipid accumulation. Intestinal FXR and the enterohepatic FGF15 signal do not contribute to the beneficial metabolic effects of FXR activation.

FGF15 - FXR - NALFD - lipid accumulation - obesity