Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice

Abstract

Farnesoid X receptor (FXR) plays an important role in maintaining bile acid and cholesterol homeostasis. Here we demonstrate that FXR also regulates glucose metabolism. Activation of FXR by the synthetic agonist GW4064 or hepatic overexpression of constitutively active FXR by adenovirus-mediated gene transfer significantly lowered blood glucose levels in both diabetic db͞db and wild-type mice. Consistent with these data, FXR null mice exhibited glucose intolerance and insulin insensitivity. We further demonstrate that activation of FXR in db͞db mice repressed hepatic gluconeogenic genes and increased hepatic glycogen synthesis and glycogen content by a mechanism that involves enhanced insulin sensitivity. In view of its central roles in coordinating regulation of both glucose and lipid metabolism, we propose that FXR agonists are promising therapeutic agents for treatment of diabetes mellitus.glucose ͉ GW4064 ͉ farnesoid X receptor-VP16 ͉ triglyceride ͉ cholesterol

Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver

“…Acute elevation of bile acids decreases liver triglycerides, 40 and synthetic FXR agonists also lower TG levels. 41 Thus, acute induction of SHP expression via the FXR pathway and either transgenic or adenoviral SHP overexpression have essentially the opposite effect on lipid accumulation. In addition, FXR Ϫ/Ϫ livers accumulate TGs despite decreased SHP expression.…”

Horizons in the Pharmacotherapy of Obesity

“…This suggests that FXR agonists should cause weight loss in diet-induced obese mice. Inconsistent results have been obtained with such compounds, however [81,82,83]. Recently, the gut-restricted FXR agonist fexaramine has been reported to reduce obesity and insulin resistance in mice.…”

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

“…Thus, there is circumstantial evidence to link the activity of FXR to the regulation of bile acid synthesis from cholesterol, providing a link between nutrient absorption and regulation of key steps in the intermediate metabolism. In addition, because bile acids might be toxic for the liver, activation of FXR by natural and synthetic ligands has been shown to prevent bile acid-induced liver toxicity in a variety of rodent models (33)(34)(35)(36)(37)(38)(39). The homeostatic function of FXR in the liver is highlighted by the demonstration that mice harboring a disrupted FXR (FXR Ϫ/Ϫ ) develop spontaneously an array of hepatocellular abnormalities including adenomas and carcinomas.…”