Bile acid retention and activation of endogenous hepatic farnesoid-X-receptor in the pathogenesis of fatty liver disease in ob/ob-mice

Abstract

The nuclear bile acid receptor FXR (farnesoid-X-receptor) has recently been implicated in the pathophysiology of nonalcoholic fatty liver disease because selective FXR-agonists improve glucose and lipid metabolism in rodent models of obesity. However, the regulation of FXR and other relevant nuclear receptors as well as their lipogenic target genes in fatty liver is still not revealed in detail. Livers were harvested from 14-week-old male ob/ob mice and wild-type controls. Serum bile acids were quantified by radioimmunoassay. mRNA and protein expression of transporters and nuclear receptors was analyzed by reverse transcriptase-polymerase chain reaction and Western blotting, whereas DNA binding to the IR-1 element was examined by electrophoretic mobility shift assay. In this study we show: (i) bile acid retention in ob/ob mice, (ii) a resulting FXR upregulation and binding to the IR-1 element in ob/ob animals and (iii) concomitant activation of the fatty acid synthase as a potential lipogenic FXR target gene in vivo. The present study suggests a potential role of hepatic bile acid retention and FXR activation in the induction of lipogenic target genes. Differences between intestinal and hepatic FXR could explain apparent contradictory information regarding its effects on fatty liver disease.

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

“…In accordance with these data from systemic Fxr −/−, the same increase in Cyp7a1 expression in combination with decreased Bsep can be observed in ΔL Fxr mice in the present study. In this context, bile acid retention due to reduced bile acid transporter expression as observed in various rodent models of fatty liver (19,20) (25). In accordance with previous data SHP is not induced in 1% cholesterol diet animals since it has been shown that SHP induction is repressed by free fatty acids (FFA) in NAFLD patients and hepatoma cells (28).…”

“…In this regard, it is also unclear whether bile acid retention and subsequent hepatic FXR activation in fatty livers represents a causal event in the pathogenesis or rather an attempt of adaptation (19,20). Following these pertinent questions we studied organspecific liver (ΔL) and intestinal (ΔIE) Fxr knockout mice under a 1% cholesterol diet.…”

Alterations in Enterohepatic Fgf15 Signaling and Changes in Bile Acid Composition Depend on Localization of Murine Intestinal Inflammation

“…Antibody staining and immune complexes detection were performed as previously described. 17 Primary antibodies used in the study were directed against basolateral Na + -dependent taurocholate cotransporting polypeptide (mNTCP 18 ), multidrug-resistance-associated protein 2 (mMRP2 19 ), bile salt export pump (BSEP 20 ), multidrug-resistance-associated protein 4 (mMRP4) (ab45602), and multidrug-resistance-associated protein 3 (mMRP3) (ab3375). Na/K-ATPase (ab7671-50) was used as a loading control.…”

Role of gut barrier function in the pathogenesis of nonalcoholic fatty liver disease

“…As a result, it can induce the lipid peroxidation and, finally, hepatic lipid accumulation. Martin and his colleagues [20] transplanted infant intestinal flora into the gut of germ-free mice and found that conjugated bile acid in terminal ileum increased and plasma lipoprotein decreased, but hepatic triglyceride increased at the same time. They inferred that the alteration of gut flora can promote the bile acid enterohepatic circulation, inhibit the synthetizing and secretion of VLDL and LDL, and result in the hepatic steatosis at last [21].…”