Identification and characterization of novel roles for the farnesoid X receptor in the adrenal gland and kidney

The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily. Bile acids have been identified as physiological ligands that activate FXR. Within the liver and intestine, FXR plays critical roles in controlling bile acid and cholesterol metabolism. Herein, we describe two approaches we undertook to elucidate the functional roles of FXR in the adrenal gland and the kidney.;First, we performed Affymetrix microarray analysis on RNA isolated from H295R, a human adrenocarcinoma cell-line, infected with adenovirus that either overexpress VP16 transactivation domain or FXR isoforms fused to VP 16 (FXR-VP16) which renders the nuclear receptor constitutively active. We identified OSTalpha and OSTbeta as genes induced in response to activated FXR. Identification of functional FXR response elements (FXREs) in the promoters of the two genes and the finding that the genes are induced in an FXR-dependent manner, both in vitro and in vivo, confirmed that OSTalpha and OSTbeta are bona fide target genes of FXR in the adrenal gland. Based on the fact that OSTalpha and OSTbeta function as a heteromeric bile acid transporter in the ileum, we hypothesize that OSTalpha and OSTbeta may function to transport bile acids into the adrenal gland and activate adrenal FXR.;The second approach utilized real-time qPCR analysis of RNA from mice treated with an FXR-specific synthetic agonist, GW4064. We identified the sodium/sulfate cotransporter (NaS-1; Slc13a1), a transporter responsible for the reabsorption of inorganic sulfates by the renal tubular cells, as a gene that was induced in mice treated with GW4064. We identified a functional FXRE in the second intron of the Slc13a1 gene and demonstrated that renal and intestinal Slc13a1 mRNA is induced in an FXR-dependent manner in vivo. More importantly, we demonstrated that FXR plays a key role in maintaining sulfate homeostasis as Fxr-/- mice display increased sulfate wasting into the urine due to decreased basal expression of Slc13a1 in the kidney.;In addition, we have recently demonstrated that FXR is also important in glucose metabolism and atherosclerosis. FXR activation significantly improved hyperglycemia and hyperlipidemia in diabetic db/db mice. Moreover, we showed that Fxr-/-/Ldlr-/- mice form less atherosclerotic lesions as compared to hyperlipidemic Ldlr-/- mice.;Together, these recent findings suggest that the physiological function of FXR is not limited to bile acid and cholesterol metabolism. Further research will be required to address the role of bile acid transport in the adrenal gland by OSTalpha/beta and the potential pharmacologic benefits of using FXR antagonists in the prevention/treatment of atherosclerosis.