Farnesoid X receptor is essential for normal glucose homeostasis

Abstract

The bile acid receptor farnesoid X receptor (FXR; NR1H4) is a central regulator of bile acid and lipid metabolism. We show here that FXR plays a key regulatory role in glucose homeostasis. FXR-null mice developed severe fatty liver and elevated circulating FFAs, which was associated with elevated serum glucose and impaired glucose and insulin tolerance. Their insulin resistance was confirmed by the hyperinsulinemic euglycemic clamp, which showed attenuated inhibition of hepatic glucose production by insulin and reduced peripheral glucose disposal. In FXR -/-skeletal muscle and liver, multiple steps in the insulin signaling pathway were markedly blunted. In skeletal muscle, which does not express FXR, triglyceride and FFA levels were increased, and we propose that their inhibitory effects account for insulin resistance in that tissue. In contrast to the results in FXR -/-mice, bile acid activation of FXR in WT mice repressed expression of gluconeogenic genes and decreased serum glucose. The absence of this repression in both FXR -/-and small heterodimer partner-null (SHP -/-) mice demonstrated that the previously described FXR-SHP nuclear receptor cascade also targets glucose metabolism. Taken together, our results identify a link between lipid and glucose metabolism mediated by the FXR-SHP cascade.

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

“…In addition, FXR Ϫ/Ϫ livers accumulate TGs despite decreased SHP expression. 42 This discrepant fatty liver phenotype between SHP Ϫ/Ϫ and FXR Ϫ/Ϫ mice reflects the complexity of the different sets of genes regulated by SHP and FXR, respectively, in controlling hepatic lipid homeostasis. It is apparent that SHP is one important component of a network of factors that modulate hepatic fat metabolism, and that alterations of SHP activity may have different effects in different circumstances.…”

The bile salt export pump

“…In the light of recent findings that bile saltmediated FXR signaling controls liver regeneration and may even control liver size [44], Bsep may move up to a key protein controlling many vital processes in liver. Furthermore, evidence that the bile acid sensor FXR is controlling glucose and lipid metabolism is rapidly accumulating [11,16,58]. Since FXR requires bile salt binding to act to control expression target genes, Bsep may, by controlling bile salt concentration in systemic circulation, become an important control element in body energy and lipid homeostasis.…”

Obesity diabetes and the role of bile acids in metabolism

“…Bile acid activation of FXR in the intestine stimulates synthesis of fibroblast growth factor (FGF) 15/19, which is involved in lipid and carbohydrate metabolism. FXR, through its downstream effect on FGF, is important in maintaining normolipidaemia, normoglycaemia, and bile acid homeostasis [9,10] . FGF inhibits CYP7A1 expression, the first step in the conversion of cholesterol to bile acids.…”