Targeted Disruption of the Nuclear Receptor FXR/BAR Impairs Bile Acid and Lipid Homeostasis

Abstract

Mice lacking the nuclear bile acid receptor FXR/BAR developed normally and were outwardly identical to wild-type littermates. FXR/BAR null mice were distinguished from wild-type mice by elevated serum bile acid, cholesterol, and triglycerides, increased hepatic cholesterol and triglycerides, and a proatherogenic serum lipoprotein profile. FXR/BAR null mice also had reduced bile acid pools and reduced fecal bile acid excretion due to decreased expression of the major hepatic canalicular bile acid transport protein. Bile acid repression and induction of cholesterol 7alpha-hydroxylase and the ileal bile acid binding protein, respectively, did not occur in FXR/BAR null mice, establishing the regulatory role of FXR/BAR for the expression of these genes in vivo. These data demonstrate that FXR/BAR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor.

The bile salt export pump

“…This leads to an upregulation of Bsep expression and consequently to increased canalicular bile salt secretion [3,32]. These data are supported by a reduced expression of Bsep in mice lacking the gene for FXR [85]. This regulatory mechanism seems to be more strongly affected by transhepatocellular bile salt flux than by steady-state bile salt levels [102].…”

Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease

“…It is widely known that an increase of triglyceride synthesis in liver plays an important role in NAFLD models [14,[21][22][23]. In rodents, an increase in the amount of synthesized lipids was observed in liver and adipose tissue cells, while in humans, it was primarily in the liver.…”

Regulation of N-Myc downstream regulated gene 2 by bile acids

“…C57BL/6J mice and Fxr-null mice [11] (FXR -/-, #007214) were obtained from The Jackson Laboratory (Bar Harbor, ME). 10-week-old male mice were injected i.p.…”