The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

I. Function of SHP in cholesterol/bile acid metabolism
The orphan nuclear receptor and transcriptional repressor, small heterodimer partner (SHP), inhibits the activities of many nuclear receptors that regulate diverse biological pathways. Our current research focuses on understanding SHP action in the regulation of key genes involved in cholesterol/bile acid metabolism. Recently we reported that SHP inhibits transcription of cholesterol 7alpha hydroxylase (CYP7A1), a key enzyme in cholesterol conversion into bile acids, by actively recruiting the chromatin modifying complexes, mSin3A/HDAC-1 and the Swi/Snf-Brm, to the promoter. Histone methyltransferase, G9a, is also recruited to the CYP7A1 promoter in a SHP-dependent manner and critically involved in SHP action. We are currently studying the functional interplay among these complexes in the inhibitory action of SHP and the roles of these complexes in bile acid metabolism. Using mouse tail vein injection of adenovirus producing flag-SHP and proteomic techniques, we are currently working on identification of SHP-interacting proteins and post-translational modification of SHP which are involved in bile acid signaling.

II. Molecular regulation of FXR activity in bile acid signaling
The overall aim of this research is to understand the function and mechanism of nuclear bile acid receptor FXR in bile acid signaling in vivo. FXR plays a central role in cholesterol/bile acid homeostasis, protecting the liver from toxic bile acids, lipid and glucose metabolism, liver regeneration, and inhibition of intestinal bacterial growth. Although such important biological functions of FXR have now been revealed, how FXR activity is regulated remains largely unknown. We are particularly interested in how FXR activity is modulated by the transcriptional cofactors, such as p300 acetylase and SIRT1 deacetylase, via acetylation of FXR itself as well as FXR target gene chromatin. Using mouse tail vein injection of adenovirus producing flag-FXR and proteomic approaches, we are also studying post-translational modification of FXR and searching for novel FXR-interacting proteins involved in bile acid-activated FXR signaling in animals in vivo.

III. Role of CAR and PXR in bile acid metabolism
The xenobiotic orphan nuclear receptors CAR and PXR play key roles in metabolism of foreign and endogenous compounds by inducing hepatic expression of cytochrome p450 enzymes. CAR and PXR have been also implicated in the suppression of hepatic bile acid biosynthesis. HNF-4 is a key transcriptional activator of hepatic genes including CYP7A1in lipid and glucose metabolism. We recently reported that PXR and CAR inhibit transcription of CYP7A1 by interfering with transactivation of the HNF-4/PGC-1alpha. CAR also inhibits CYP7A1 by inhibiting binding of HNF-4 to the DNA. We are now working on identification of functional CAR/PXR target genes involved in bile acid metabolism using chromatin immunoprecipitation/cloning techniques. We are also studying effects of different bile acids on post-translational modification of CAR/PXR in animals in vivo.

Our studies should provide critical insights into delineating roles of orphan nuclear receptors in controlling hepatic cholesterol/bile acid metabolism and should help to design novel therapeutic agents for treatment of metabolic disorders.