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

Orphan nuclear receptors belong to the nuclear receptor superfamily based on their sequence similarity, but their respective ligands and target genes and their physiological function were unknown initially.  However, recent advances in these fields unveiled surprising roles of these receptors in cellular metabolism including cholesterol/bile acid, glucose, and drug metabolism.  We are studying the functions of nuclear receptors and their cofactors in metabolic regulation using mouse models, as well as, molecular and cellular approaches.  We are focusing on two nuclear receptors, the nuclear bile acid receptor, Farnosoid X receptor (FXR), and a metabolic repressor, Small Heterodimer Partner (SHP).

I. Molecular regulation of FXR activity in health and disease

The overall aim of this research is to understand how FXR regulates metabolic homeostasis in normal and disease states.  FXR plays a critical role in maintaining lipid and glucose levels by regulating its metabolic target genes in the liver and intestine.  Although the critical functions of FXR are known, how FXR activity is regulated remains largely unknown.  Using animal studies, along with molecular and cellular studies, we have discovered an important regulatory role for acetylation of FXR in normal and metabolic disease states.  FXR acetylation inhibits its activity and is normally dynamically regulated by p300 acetylase and SIRT1 deacetylase but is constitutively elevated in metabolic disease states.  Small molecules that inhibit FXR acetylation by targeting p300 and SIRT1 may be useful for treating metabolic disorders.  Using proteomic approaches, we continue to study post-translational modifications of FXR and are also searching for novel FXR-interacting proteins involved in FXR signaling pathways in normal and disease states.  A second focus is studies of how FXR may regulate its target genes in a gene-selective manner by controlling expression of microRNAs. MicroRNAs are emerging cellular regulators critically involved in diverse biological pathways, including metabolic regulation, cell proliferation, and apoptosis.  Approximately 30% of all human genes are thought to be regulated by microRNAs and aberrant expression of microRNAs has been detected in pathophysiological conditions.  We have identified microRNAs whose expression is specifically regulated by FXR in liver.  Therefore, we are interested in determining roles of these microRNAs in metabolic regulation in health and disease states.

II. SHP action in metabolic regulation: Physiology and Mechanism.

The overall aim of this project is to understand how cholesterol and bile acid levels are regulated by SHP in the liver.  Recently we reported that SHP inhibits transcription of cholesterol 7α hydroxylase (CYP7A1), a key enzyme in the conversion of cholesterol into bile acids, by coordinately recruiting chromatin modifying complexes, including the corepressors mSin3A/HDAC- 1, histone lysine methyltransferase G9a, and the Swi/Snf-Brm chromatin remodeling complex.  We are studying how these chromatin modifying cofactors mediate SHP-mediated transcriptional inhibition of its metabolic target genes.  In addition, we are studying how SHP activity in the liver is modulated by post-translational modifications.  It has been well established that bile acids increase SHP gene induction, but we recently discovered that regulation of SHP stability is also important in modulating SHP levels.  SHP is rapidly degraded in hepatocytes, and bile acids and bile acid-induced FGF19 signaling pathways increase SHP stability by inhibiting its ubiquitination and proteasomal degradation.  Using biochemical and proteomic approaches, we are continuing to study post-translational modifications of SHP and also searching for novel SHP-interacting proteins involved in metabolic regulation in normal and disease states.

III. Novel Regulatory Networks Controlling Hepatic Lipid Metabolism through SIRT1

Nutrient-sensing SIRT1 deacetylase regulates cellular metabolism, stress response, and possibly, aging in response to nutritional and hormonal fluctuations.  Despite extensive studies on SIRT1 function, how SIRT1 levels and activity are regulated remains relatively unknown.  We recently discovered that the nuclear bile acid receptor FXR positively regulates hepatic SIRT1 by inhibiting small non-coding microRNA-34a (miR-34a).  We further found that an intriguing positive feedback FXR/SIRT1 regulatory network is operating in normal hepatocytes, which reinforces each other’s expression and activity.  Manipulation of this novel regulatory network may be useful for treating diseases of aging, such as diabetes, obesity, and cancer. 

Our studies to delineate the molecular basis of transcriptional signaling by these nuclear receptors and their cofactors in health and disease states should reveal novel molecular targets for treating metabolic disorders, such as, hypercholesterolemia, fatty liver, obesity, and diabetes.