Research Topics

Chromatin Structure, Endocrinology, Genomics, Metabolic Regulation, Regulation of Gene Expression, Signal Transduction

Disease Research Interests

Aging Related Diseases, Metabolic Disorders/Diabetes

B.S., Seoul National University, Korea
Ph.D., University of Illinois at Urbana-Champaign
Postdoc., University of Illinois at Urbana-Champaign
Postdoc., Stanford University

Metabolic Signaling and Epigenomic Control of Metabolism and Energy Balance

Maintaining a normal range of cholesterol, bile acid (BA), fat, and glucose in the body is essential for human health. Disruption of lipid and glucose levels causes metabolic diseases, such as, obesity, type II diabetes, cardiovascular disease, hepatobiliary disease, and even, certain types of cancers. My laboratory is studying how these metabolite levels are regulated by the bile acid signal-sensing nuclear receptors, Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP), and epigenomic regulators, including SIRT1, JMJD3, and DNMT3A and microRNAs, in normal conditions and how their functions are dysregulated in metabolic diseases. We hope our findings will aid the development of novel therapeutic and diagnostic agents for fighting metabolic disorders.

I. Novel Functions of FXR in Physiology and Disease

Bile acid (BAs) are recently recognized key endocrine signaling molecules that control metabolism and energy balance. FXR is the primary biosensor for BAs and plays a central role in maintaining bile acid homeostasis. To explore new functions of FXR, we examined hepatic binding sites for FXR in the entire mouse genome by ChIP-seq analysis and were able to identify previously unknown functions of FXR, including hepatic autophagy. In recent studies (Nature, 2014; EMBO J, 2017), we found that the fed-state sensing nuclear receptor FXR and the fasting transcriptional activator CREB coordinately regulates the hepatic autophagy gene network and that CREB and FXR oppositely regulate autophagic degradation of lipid (lipophagy). In addition, we have shown the functional role of post-translational modifications (PTMs) in modulating transcriptional activity of FXR. In recent studies (EMBO J, 2014), we showed that elevated acetylation of FXR in obesity inhibits its SUMOylation, which alters transcriptional programs that leads to hepatic inflammation and metabolic dysfunction. We continue to study to determine the in vivo role of signal-induced PTMs in modulating transcriptional functions of FXR in physiology and disease.

II. Functions and Mechanisms of SHP in Regulating BA levels

The goal of this project is to understand how cholesterol and BA levels are regulated by SHP in the liver. We have shown that SHP inhibits transcription of cholesterol 7α hydroxylase (CYP7A1), a key enzyme in the conversion of cholesterol into BAs, by coordinately recruiting chromatin modifying enzymes, including HDACs, G9a, and LSD1. We are investigating the in vivo role of these enzymes in regulating BA levels and protecting liver against BA toxicity. In addition, we are studying how SHP stability and repression activity is regulated by BA signal-induced PTMs. Further, to identify global SHP binding sites and its novel functions in mouse liver, we performed genome-scale ChIP-seq and RNA-seq studies. These unbiased comprehensive analyses have revealed exciting potential new functions of SHP. We are currently examining these novel functions of SHP and its mechanisms. Also, SHP has been designated an orphan nuclear receptor, but whether its activity can be modulated by ligands has been a long-standing question. Recently, we reported that atypical retinoids, including 3Cl-AHPC, act as agonists that increase SHP activity. In continued studies, we are searching for endogenous ligand(s) of SHP.

III. Regulation of SIRT1 in Physiology and Disease

Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that functions as a key metabolic/energy sensor and mediates homeostatic responses to nutrient availability. Mounting evidence indicates that SIRT1 shows beneficial impacts on metabolism and energy balance. Importantly, SIRT1 activity and levels are decreased in obesity and aged animals but the underlying mechanisms are largely unknown. Our group has shown that SIRT1 is a critical determinant of acetylation levels of FXR and SREBP-1c and modulate their activity in regulation of metabolic pathways. For example, deacetylation of SREBP-1c decreases its gene activity by inhibiting DNA binding and promoting protein degradation. We further showed that SIRT1 levels and activity are decreased by microRNA-34a, which is highly elevated in obesity. We continue to study how SIRT1 expression and activity are dynamically regulated during fasting/feeding cycles in physiological conditions and how dysregulated in metabolic diseases.

IV. MicroRNAs as Key Regulators of Energy Metabolism and Liver Injury

MiR-34a is highly elevated in obese animals and also in obesity patents. We have shown that elevated miR-34a underlies metabolic dysfunction associated with obesity. Particularly, in recent studies (MCB, 2014), we show that elevated miR-34a in obesity inhibits fat browning by suppressing the browning activators, FGF21 and SIRT1. Downregulation of miR-34a in diet-induced obese mice reduced adiposity and increased mitochondria functions. Strikingly, downregulation of miR-34a dramatically increased beige depots in all types of white fats and increased additional browning in brown fat. Mechanistically, downregulation of miR-34a increased expression of the FGF21 receptor complex, FGFR1/βKL, and SIRT1, resulting in deacetylation of the key thermogenic coactivator PGC-1α and induction of the browning-related genes, Ucp1, Pgc-1a, and Prdm16. In previous studies, we also showed that downregulation of miR-34a dramatically decreased liver fat levels and improved insulin sensitivity. Targeting miR-34a may provide an attractive option for treating obesity-related diseases, including fatty liver and type 2 diabetes.

Department of Molecular & Integrative Physiology
524 Burrill Hall
407 S. Goodwin Ave
Urbana, IL 61801