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

Abnormally elevated cholesterol, bile acid, fat, and glucose levels due to the disruption of metabolic homeostasis play causative roles in the development of metabolic disease, such as fatty liver, obesity, type II diabetes, and cancer. The main research goal of my laboratory is to understand how these metabolite levels are regulated by nuclear receptors (NRs)at the genomic and epigenomic levels. My lab focuses on two NRs, the bile acid receptor, Farnesoid X Receptor (FXR), and a metabolic repressor, Small Heterodimer Partner (SHP). Using multidisciplinary approaches from cell-free to whole animal studies utilizing molecular biological, as well as proteomic and genomic approaches, we are studying how NR transcriptional signaling pathways are dynamically regulated under physiological conditions and how they are dysregulated in metabolic disease states. Our studies to delineate the molecular basis of transcriptional signaling by these nuclear receptors and their cofactors in health and disease should reveal novel molecular strategies for treating metabolic diseases.

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. 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 highly 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.

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 cofactors, including the HDACs-containing mSin3A and NcoR corepressor complexes, 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 levels and activity is modulated by post-translational modifications. 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 and microRNAs

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.

Representative Publications

T. Fu, S.Choi, D. Kim, S. Seok, K. Suino-Powell, H. Xu, and J. K. Kemper. (2012) Aberrantly elevated miR-34a in obesity attenuates hepatic responses to FGF19 by targeting a membrane coreceptor beta-Klotho, PNAS, in press.

Z. Smith#, D. Ryerson#, and J. K. Kemper. (2012) (# these authors contributed equally to this study). Epigenomic Regulation of Bile Acid Metabolism:Emerging Role of Transcriptional Cofactors, Invited review, Molecular Cellular Endocrinology,in press.

J. Lee#, S.M. Seok#, P. Yu, K. Kim, Z. Smith, M. Rivas-Astroza, S. Zhong, and J. K. Kemper. (2012) (# these authors contributed equally to this study). Genomic analysis of hepatic Farnesoid X Receptor (FXR) binding sites reveals altered binding in obesity and direct gene repression by FXR, Hepatology, in press.

A. Purushotham, Q. Xu, J. Lu, J. Foley, X. Yan, D.H. Kim, J. K. Kemper, and X. Li (2012) Hepatic deletion of SIRT1 decreases HNF1α/FXR signaling and induces formation of cholesterol gallstones in mice, Molecular and Cellular Biology, in press.

J. Miao#, SE Choi#, SM Seok, L.Yang, W.Zuercher, Y.Xu, T.Willson, H. E.Xu, and J. K. Kemper .(2011) (# these authors contributed equally to this study). Ligand-dependent regulation of the activity of the orphan nuclear receptor, Small Heterodimer Partner (SHP), in the repression of bile acid biosynthetic CYP7A1 and CYP8B1 genes, Molecular Endocrinology , 25:1159-1169.

J. K. Kemper . (2011) Regulation of FXR Transcriptional Activity in Health and Disease: Emerging Roles of FXR Cofactors and Post-Translational Modifications. Invited review, Biochimia et Biophysica Acta,1812:842-850.

D. Kanamaluru, Z. Xiao, S. Fang, S. Choi, D.Kim, T. Veenstra, and J. K. Kemper .(2011) Arginine methylation by PRMT5 at a naturally-occurring mutation site is critical for metabolic regulation by Small Heterodimer Partner. Molecular and Cellular Biology, selected as a spotlight paper, 31, 1540-1550.

B. Ponugoti#, D. Kim#, Z. Smith, J. Miao, M. Zang, S. Y. Wu, C. M. Chiang, T. D. Veenstra, and J. K. Kemper. (2010)(# these authors contributed equally to this study), SIRT1 deacetylates and inhibits SREBP-1c activity in regulation of hepatic lipid metabolism. J. Biol Chem, 285: 33959-70.

J. Lee and J. K. Kemper. (2010) Controlling SIRT1 expression by microRNAs in health and metabolic disease. Invited review, Aging, 2: No 8, 1-8.

J. Lee, A. Padhye#, A. Sharma#, G. Song#, J. Miao, Y. Mo, L. Wang, and J. K. Kemper. (2010) (# these authors contributed equally to this study), FXR inhibition of MiR-34a expression positively regulates hepatic SIRT1 levels, J. Biol Chem, 285, 12604-12611.

J. K. Kemper (also corresponding author), Z.Xiao#, B.Ponugoti#, J. Miao #, S. Fang, D. Kanamaluru, S. Tsang, S. Wu, C. M. Chiang, and T. D. Veenstra. (2009) (# these authors contributed equally to this study). FXR acetylation is normally dynamically regulated by p300 and SIRT1 but is constitutively elevated in metabolic disease states. Cell Metabolism, 10, 392-404. Selected as an Editor's Choice by Science Signaling. Selected as a Faculty of 1000 Recommended Article

J.Miao, S. Fang, J. Lee, C. Comstock, K. E. Knudsen, and J. K. Kemper. (2009) Functional specificity of Brm and Brg-1 Swi/Snf ATPases in the feedback regulation of hepatic bile acid biosynthesis. Mol. Cell. Biol., 6170-6181.

J. Miao, Z. Xiao, D. Kanamaluru, G. Min, P. M. Yau, T. D. Veenstra, E.Ellis, S. Strom, K. Suino-Powell, E. Xu, and Kemper JK. (2009), Bile acid signaling pathways increase stability of Small Heterodimer Partner (SHP) by inhibiting ubiquitin-proteasomal degradation. Genes and Development, 23:986-996 Selected as a Faculty of 1000 Recommended Article.

Fang S., Tsang S., Jones R., Ponugoti B., Yoon H., Wu S., Chiang C.M., Willson T. M., and Kemper JK. (2008) The p300 acetylase is critical for ligand-activated Farnosid X receptor (FXR) induction of SHP. J. Biol Chem. 283: 35086-95.

Ponugoti B, Fang S, and J. K. Kemper. (2007) Functional interaction of HNF-4 and PGC-1a in CYP7A1 regulation is inhibited by a key lipogenic activator, SREBP-1c. Molecular Endocrinology, 21, 2698-2712, 2007.

Fang S, Miao J, Xiang L, Ponugoti B, Treuter E, and Kemper JK. (2007) Coordinated recruitment of histone methyltransferase G9a and other chromatin modifying enzymes in SHP-mediated regulation of hepatic bile acid metabolism. Mol. Cell. Biol. 27:1407-1424.

Complete Publications List