New horizons in the regulation of bile acid and lipid homeostasis: critical role of the nuclear receptor FXR as an intracellular bile acid sensor

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Abstract
Building on the recent discovery that FXR is a BA activated nuclear receptor that can regulate expression of BA responsive target genes in the intestine and liver,11 , 12 the paper by Sinalet al explores the effects of FXR deficiency in vivo and therefore provides an important physiological setting for the central role of FXR in controlling BA homeostasis. Using now standard genetic ablation techniques, FXR −/− mice were generated. Knockout mice were viable, fertile, grew normally, and exhibited elevated serum levels of BA, cholesterol, and triglycerides, increased hepatic cholesterol and triglyceride levels, a reduced bile acid pool size, and decreased faecal bile acid excretion. This phenotype indicates that defective hepatic uptake and excretion of BA are present in FXR −/− mice and that FXR has a profound influence on lipid metabolism. In fact, when the authors assessed expression of genes involved in hepatic and ileal BA transport as well as genes controlling BA biosynthesis, they found a significant decrease in mRNA levels of the major BA transporter at the canalicular membrane, the bile salt export pump (Bsep) and the putative intracellular intestinal transporter of bile acids (the ileal bile acid binding protein) while CYP7A1 message was increased. Together, these data indicate that under basal conditions, FXR is required for normal expression of these genes. To further study the influence of FXR on BA and lipid homeostasis, Sinal et al fed control and FXR −/− mice with either BA (1% cholic acid) or cholesterol enriched chow. On dietary challenge with cholic acid, FXR −/− mice developed severe hepatotoxicity with marked vacuolation and necrosis of liver cells on histological analysis reflecting an inability of the knockout mice to deal with BA overload. In contrast, normal mice tolerated well administration of cholic acid and did not show overt signs of toxicity. When expression of genes involved in BA metabolism was analysed, normal mice responded to BA feeding with downregulation of CYP7A1 and Ntcp mRNA levels, and upregulation of Bsep mRNA, while null animals were unable to display these changes in gene expression. These findings suggest that the regulatory response of hepatocytes to BA overload consists of reducing BA synthesis and import, and increasing BA export. These data indicate that FXR plays a fundamental role in protecting the liver against pathophysiological levels of BA. In addition, Sinalet al observed that FXR deficiency is associated with a significant reduction in mRNA levels of the BA activated transcriptional repressor SHP (small heterodimer partner) which is known to mediate CYP7A1 and Ntcp downregulation.8 , 10 On BA feeding of wild-type mice, SHP expression was markedly upregulated while FXR −/− mice were again unable to display this response. This observation confirms that SHP expression is under direct control of FXR.10