524 Burrill Hall
407 S. Goodwin Ave
Urbana, IL 61801
Chromatin Structure, Endocrinology, Genomics, Metabolic Regulation, Regulation of Gene Expression, Signal Transduction
Disease Research Interests
Aging Related Diseases, Metabolic Disorders/Diabetes
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.
B.S., Seoul National University, Korea
Ph.D., University of Illinois at Urbana-Champaign
Postdoc., University of Illinois at Urbana-Champaign
Postdoc., Stanford University
MCB 465 - Human Metabolic Disease
Additional Campus Affiliations
Seok S, Kim Y, Zhang Y, Kong B, Guo G, Ma J, Kemper B, and Kemper, JK. (2022) Feeding activates FGF15-SHP-TFEB-mediated lipophagy in the gut. EMBO Journal, e109997.
Highlighted in News and Views, EMBO Journal,, 2022, Feeding and lipophagy: it takes guts to deliver", by Nuno Raimundo, e112180. Seok S, and Kemper, JK. (2022) Paradoxical feeding activation of gut lipophagy by FGF15/FGF19-NR0B2/SHP-TFEB, Highlighted in Autophagy, , DOI: 10.1080/15548627.2022.2108296
Seok S, Sun H, Kim Y, Kemper B, and Kemper, JK. (2021) Defective FXR-SHP regulation in obesity aberrantly increases miR-802 expression, promoting insulin resistance and fatty liver. Diabetes. 70(3):733-744.
Jung H, Chen J, Hu X, Sun H, Wu S, Chiang C, Kemper B, LF Chen and Kemper, JK. (2021) (LF Chen and JK Kemper are co-coresponding authors). BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination. JCI Insight, 6 (1) e141640
Kim YC, Seok S, Zhang Y, Ma J, Kong B, Guo G, Kemper B and Kemper, JK. (2020). Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A, Nature Communications 11, 5969.
Byun S*, Seok S*, Kim Y, Zhang Y, Ma J, Yau P, Iwamori N, Xu HE, Kemper B and Kemper, JK. (2020) (*Byun and Seok equally contributed to this study). Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase. Nature Communications, 11:807. doi: 10.1038/s41467-020-14384-z. Selected as the Editors' Highlighted Paper in the Genome/Epigenome area.
Kim Y*, Jung H*, Seok S, Zhang Y, Ma J, Li T, Kemper, B, and Kemper, JK. (2019) (*Kim and Jung equally contributed to this study). MicroRNA-210 promotes bile acid-induced cholestatic liver injury by targeting MLL4 methyltransferase in mice. Hepatology, . doi: 10.1002/hep.30966.
Kim YC, Byun S, Seok S, Guo G, Xu E, Kemper B, and J.K. Kemper. (2019) (YC Kim and JK Kemper, coresponding authors). Small Heterodimer Partner and Fibroblast Growth Factor-19 Inhibit Intestinal Npc1l1 Expression and Cholesterol Absorption.Gastroenterology,156:1052-1065. doi: 10.1053/j.gastro.2018.11.061.
Seok, S, Kim,YC, Byun, S, Choi, S, Xiao, Z, Iwamori, N, Zhang, Y, Wang, C, Ma, J, Ge, K, Kemper, B, and J.K. Kemper (2018). Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid β-oxidation, J. Clinical Investigation,128:3144-3159. Selected as a Highlighted Paper.
Byun S, Kim D, Ryerson D, Kim Y, Sun H, Kong B, Yau P, Guo G, Xu E, Kemper B, and J.K. Kemper (2018). (Byun, Kim, and Ryerson equally contributed to this study). Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis. Nature Communications, 9: 2590.
Kim YC, Seok S, Byun S, Kong B, Zhang Y, Guo G, Xie W, Ma J, Kemper B, and J.K. Kemper (2018). (YC Kim and JK Kemper, coresponding authors), AhR and Shp regulate Phosphatidylcholine and S-Adenosyl methionine Levels in the One-Carbon Cycle. Nature Communications, 9:540 doi:10.1038/s41467-018-03060-y.
Byun S, Kim YC, Zhang Y, Kong B, Guo G, Sadoshima J, Ma J, Kemper B, and J.K. Kemper (2017) A postprandial FGF19-SHP-LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy, EMBO Journal, 36, 1465-1642.
Choi S, Kwon S, Seok S, Xiao Z, Lee K, Kang Y, Li X, Shinoda K, Kajimura S, Kemper B, and J.K. Kemper (2017) (CS, KS, SS equally contributed to this study). Obesity-linked phosphorylation of SIRT1 by CK2 inhibits its nuclear localization and promotes fatty liver, Molecular and Cellular Biology, Jul 14;37(15).10.1128/MCB.00006-17 Selected as the Spotlight Paper.
Kwon S, Seok S, Yau P, Li X, Kemper B, and J.K. Kemper (2017). (Kwon and Seok equally contributed to this study), Obesity and aging diminish SIRT1-mediated deacetylation of SIRT3, leading to hyperacetylation and decreased activity and stability of SIRT3, Journal of Biological Chemistry,292:17312-17323. doi: 10.1074/jbc.M117.778720.
Kim DH, Kwon S, Byun S, Xiao Z, Park S, Wu S, Chiang C, Kemper B, and J.K. Kemper (2016). Critical role of RanBP2-mediated SUMOylation of SHP in maintaining bile acid homeostasis, Nature Communications, 14;7:12179 doi: 10.1038/ncomms12179.
Kim Y, Byun S, Zhang Y, Seok S, Kemper B, Ma J, J.K. Kemper (2015). (Kim, Byun, and Zhang equally contributed to this study; Ma and Kemper are co-corresponding authors), Liver ChIP-seq analysis in FGF19- treated mice reveals SHP as a global transcriptional partner of SREBP-2. Genome Biology, 16:268.
Kim Y, Fang S, Byun S, Seok S, Kemper B, and J. K. Kemper (2015) FXR-induced lysine-specific histone demethylase, LSD1, reduces hepatic bile acid levels and protects the liver against bile acid toxicity. Hepatology , 62, 220-231. Editorial Comments in Hepatology, "Bile acid hepatotoxicity: Epigenetics comes to the rescue", 2015, 62:22-4.
Seok S, Fu T, Choi SE, Li Y, Zhu R, Kumar, S, Sun X, Yoon G, Kang Y, Zhong W, Ma, J, Kemper B, and J. K. Kemper (2014) (Seok and Fu equally contributed to this study), Transcriptional regulation of autophagy by an FXR/CREB axis. Nature, 516(7529):108-11. doi: 10.1038/nature13949. Highlighted in News and Views, Nature, 2014, Cell metabolism: Autophagy transcribed, doi:10.1038/nature13939. Highlighted in Nature Reviews Endocrinology, 2014, Nutrient-sensing and autophagic genes in fed and fasted states, doi:10.1038/nrendo.2014.212.,
Kim DH, Xiao Z, Kwon S, Sun X, Tkac D, Ryerson D, Choi SE, Ma P, Wi S, Chiang CM, Palvimo J, Chen LF, Kemper B, and J. K. Kemper (2014) A dysregulated Acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity. EMBO Journal,34:184-99. doi: 10.15252/embj.201489527.
Fu T, Seok S, Choi S, Huang Z, Suino-Powell K, Xu E, Kemper B, and J. K. Kemper(2014) MiR-34a inhibits beige and brown fat formation in obesity in part by suppressing adipocyte FGF21 signaling and SIRT1 function, Molecular and Cellular Biology, 34:4130-42. doi: 10.1128/MCB.00596-14. Selected as the Spotlight Paper.
Seok SM, Kanamaluru D, Xiao Z, Ryerson D, Choi S, Suino-Powell K, Xu E, Veenstra T., J. K. Kemper (2013). Bile acid signal-induced phosphorylation of Small Heterodimer Partner by Protein Kinase C-zeta is critical for epigenomic regulation of liver metabolic genes. Journal of Biological Chemistry, 288(32): 23252-63.
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. Proceedings of the National Academy of Sciences, USA, 109:16137-42.
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. Journal of Biological Chemistry, 285: 33959-70.
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 and Highlighted in Science Signaling.
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
Choi, S. E., Hwang, Y., Lee, S. J., Jung, H., Shin, T. H., Son, Y., Park, S., Han, S. J., Kim, H. J., Lee, K. W., Lee, G., Kemper, J. K., Song, H. K., & Kang, Y. (2022). Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in mice. Journal of Hepatology, 77(3), 735-747. https://doi.org/10.1016/j.jhep.2022.03.034
Seok, S., Kim, Y. C., Zhang, Y., Kong, B., Guo, G., Ma, J., Kemper, B., & Kemper, J. K. (2022). Feeding activates FGF15-SHP-TFEB-mediated lipophagy in the gut. EMBO Journal, 41(17), [e109997]. https://doi.org/10.15252/embj.2021109997
Seok, S., & Kemper, J. K. (Accepted/In press). Paradoxical feeding activation of gut lipophagy by FGF15/FGF19-NR0B2/SHP-TFEB. Autophagy. https://doi.org/10.1080/15548627.2022.2108296
Hu, X., Dong, X., Li, G., Chen, Y., Chen, J., He, X., Sun, H., Kim, D. H., Kemper, J. K., & Chen, L. F. (2021). Brd4 modulates diet-induced obesity via PPARγ-dependent Gdf3 expression in adipose tissue macrophages. JCI Insight, 6(7), [e143379]. https://doi.org/10.1172/jci.insight.143379
Jung, H., Chen, J., Hu, X., Sun, H., Wu, S. Y., Chiang, C. M., Kemper, B., Chen, L. F., & Kemper, J. K. (2021). BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination. JCI Insight, 6(1), [e141640]. https://doi.org/10.1172/jci.insight.141640