John Y.L. Chiang, Ph.D.
Professor of Biochemistry and Molecular Pathology
Department of Integrative Medical Sciences
Ph.D., State University of New York at Albany, N.Y. - 1976
B.S., National Taiwan Chung-Shing University, Taiwan - 1969
Professor of Biochemistry and Molecular Pathology, Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio - 1988-present
Associate Professor of Biochemistry and Molecular Pathology, Department of Biochemistry, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio - 1983-1988
Graduate Faculty, Cellular and Molecular Biology Program (Chair, 2000-present), Pharmacology Program, School of Biomedical Sciences, Kent State University - 1978-present
Assistant Professor of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio - 1978-1983
Postdoctoral Scholar, Supervisor (with Dr. M.J. Coon), Department of Biological Chemistry, The university of Michigan Medical School, Ann Arbor, Mich. - 1976-1978
Nuclear receptor regulation of bile acid metabolism in liver diseases, diabetes and obesity.
The PI has over 30 years research experiences in studying bile acid metabolism and regulation. His laboratory has made major contribution in purification and cloning of cholesterol 7a-hydroxylase gene (CYP7A1) and studying the molecular mechanism of bile acid feedback regulation of bile acid synthesis by bile acid-activated nuclear receptors, and bile acid signaling in regulation of glucose, lipid, and energy metabolism. Over the years, his laboratory has adopted molecular biology techniques to study transcriptional regulation of bile acid biosynthesis genes CYP7A1, CYP8B1, CYP27A1, and CYP7B1. Then he used a primary human hepatocyte model to study regulation of bile acid synthesis in human liver. More recently, his laboratory is using Cyp7a1-/-, Fxr-/-, and Tgr5-/- mouse models to study bile acid metabolism, liver inflammation, non-alcoholic fatty liver disease, and diabetes and obesity. The PI's laboratory has generated Cyp7a1-transgenic mice and demonstrated that increasing bile acid pool deficient of cholic acid prevented Western high fat diet-induced fatty liver, insulin resistance and obesity. His recent studies showed that increasing bile acid synthesis stimulated de novo cholesterol synthesis but maintained cholesterol and triglyceride homeostasis. In summary, the PI has demonstrated a long record of highly productive and innovative research in bile acid metabolism.
Honors and Awards:
1977-1978 National Research Service Award, NIH
2001 Faculty Research Award, NEOMED.
2011 MERIT Award, NIDDK, NIH.
2013 Distinguished University Professor, NEOMED.
2014 Liebelt/Wheeler Award for Faculty Excellence, NEOMED
1990-1996 American Heart Association Ohio Affiliates study section
1996-2000 NIH Biochemistry Study Section member
2000- Ad hoc reviewer of various study sections (Pharmacology, Endocrine and Nutrition), Special Emphasis Panels (ZRG, DKUS, Cardiovascular Science SBIR); Program project grants, Conference grant review; VA Cardiology A, GAST Study Sections.
2002-2004 AASLD Basic Research Committee
2004-2008 Hepatobiliary pathobiology (HBPP) Study Section member
2004- NIDDK Action Plan for Liver Disease Research Working group 1D: bile, bile acids, bilirubin, and cholestasis.
2004- Editorial Board: Hepatology
2005-2006 American Heart Associate Ohio Valley Affiliate Research Committee.
2006-2008 Secretary/Treasurer, Drug Metabolism Division, ASPET.
2006- External Advisory Board, NIH COBRE grant, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center.
2007-2012 Editorial Board: J. of Biol. Chem.
2011-2015 VA Merit review GAST study section
2012- Associate Editor, Drug Metabolism Review
2013- 2016 Member, Public and Clinical Policy Committee, AASLD
2015- Consultant: current- NGM Biopharmaceutical, South San Francisco; Resverlogix Corp, Calgary, Alberta, Canada.
ASBMS, ASPET, AAAS, AASLD, ISSX, SCBA, AGA, ADA
Truncated human cholesterol 7α-hydroxylase, method of production and use thereof. (U.S. Patent #5,420,028 issued on May 30, 1995, European Patents: No. 0648842, issued 2003).
Cholesterol 7α-hydroxylase gene regulatory elements and methods of using them. (U.S. Patent #5,558,999 issued September 24, 1996).
Genomic DNA of human cholesterol 7α-hydroxylase, and methods of using it. (U.S. Patent #5,650,286 issued July 22, 1997).
Transgenic mice expressing human cholesterol 7α-hydroxylase (U.S. Patent #5,663,483, issued September 2, 1997)
Genomic DNA of human cholesterol 7α-hydroxylase, and methods of using it. (U.S. Patent #5,677,159 issued October 14, 1997).
Cholesterol 7α-hydroxylase gene regulatory elements and transcriptional factors. (U.S. Patent #5,753,431, issued May 19, 1998)
Assay for agents that affect cholesterol 7α-hydroxylase expression and a characterization of its regulatory elements (US patent #5,821,057, issued October 13, 1998)
Genomic DNA of human cholesterol 7α-hydroxylase and method for using it. (US patent #5,851,780, issued December 22, 1998)
Contributions to Science
Purification and cloning of cholesterol 7-hydroxylase gene (CYP7A1). We purified CYP7A1 from rat liver microsomes and generated a specific antibody against CYP7A1, which was used to clone the CYP7A1 genes and study molecular mechanism of transcriptional regulation of CYP7A1 gene expression. These are landmark and breakthrough studies in early 1990s that contributed significantly to our current understanding the molecular mechanisms of bile acid feedback regulation and bile acid signaling in lipid homeostasis and identification of bile acid-activated nuclear receptors in 2000s.
a. Chiang, J. Y. L., Miller, W. F. and Lin, G. -M. Regulation of Cholesterol 7a-hydroxylase in the Liver. Purification of Cholesterol 7a-hydroxylase and the Immunochemical Evidence for the Induction of Cholesterol 7-hydroxylase by Cholestyramine and Circadian Rhythm. J. Biol. Chem. 265, 3889-3897 (1990).
b. Li, Y. C., Wang, D. P. and Chiang, J. Y. L. Regulation of Cholesterol 7a-hydroxylase in the Liver. cDNA Cloning, Sequencing and Regulation of Cholesterol 7a-hydroxylase mRNA. J. Biol. Chem., 265, 12012-12019 (1990).
c. Pandak, W. M., Li, Y. C., Chiang, J. Y. L., Studer, E. J., Gurley, E. C., Heuman, D. M., Vlahcevic, Z. R. and Hylemon, P. B. Regulation of Cholesterol 7a-hydroxylase mRNA and Transcriptional Activity by Bile Salts in the Chronic Bile Fistula Rat. J. Biol. Chem. 266, 3416-3421 (1991).
d. Li, Y. C. and Chiang, J.Y.L. The Expression of Catalytically Active Cholesterol 7a-hydroxylase Cytochrome P450 in E. coli. J. Biol. Chem. 266, 19186-19191 (1991).
Study of nuclear receptor regulation of bile acid synthesis gene transcription. We performed detailed study of the underlying mechanism of nuclear receptor regulation of bile acid biosynthesis genes CYP7A1, CYP8B1, CYP7B1 and CYP27A1 genes. We identified binding sites of FXR, LXR, PPAR and HNF4 in gene promoters. We studied human CYP7A1 and discovered that human CYP7A1 gene is not regulated by cholesterol receptor LXRα. We identified two BAREs located in the proximal promoter of CYP7A1 gene. These BAREs contain putative nuclear receptor binding sites. We proposed that bile acid might activate a receptor that indirectly inhibited CYP7A1 gene transcription by interacting with a transcriptional repressor. This model was later supported by the identification of FXR as a bile acid activated receptor and SHP as a repressor of CYP7A1 gene transcription. We also showed that intra duodenal, but not intravenous infusion of bile acids inhibited CYP7A1 gene transcription. This study suggested that an intestinal factor might be required for bile acid feedback regulation of bile acid synthesis. This was confirmed ten years later in 2010 that an intestinal FXR-induced FGF15/19 may inhibite bile acid synthesis in the liver.
a. Chiang, J. Y. L. and Stroup, D. Identification and Characterization of a Putative Bile Acid Responsive Element in Cholesterol 7a-Hydroxylase Gene Promoter. J. Biol. Chem. 269, 17502-17507 (1994).
b. Pandak, W. M., Heuman, D. M., Hylemon, P. B., Chiang, J. Y. L., and Vlahcevic, Z. R. Failure of Intravenous Infusion of Taurocholate to Down-Regulate Cholesterol 7-α hydroxylase in rats with Biliary Fistulas. Gastroenterology. 108, 533-544 (1995).
c. Chiang, J. Y. L., R. Kimmel, C. Weinberger, and D. Stroup. “FXR responds to bile acids and represses cholesterol 7a-hydroxylase gene (CYP7A1) transcription”. J. Biol. Chem. 275, 10918-10924 (2000).
d. Chiang, J. Y. L., Kimmel, R. and Stroup, D. Regulation of cholesterol 7a-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor LXR. Gene, 257-265. (2001).
Study regulation of human CYP7A1 and CYP8B1 gene transcription. We studied human CYP7A1 and CYP8B1 gene regulation and showed very different regulation from rodent genes. We used human primary hepatocytes as a model system to study human CYP7A1 gene regulation. Our results showed that cytokine strongly inhibited CYP7A1 and CYP8B1 gene transcription and identified JNK/cJun pathway was involved in regulation.
a. Chen, W., Owsley, E., Yang, Y., Stroup, D. and Chiang, J. Y. L. Nuclear receptor-mediated repression of the human cholesterol 7a-hydroxylase gene (CYP7A1) transcription by bile acids. J. Lipid Res. 42, 1402-1412 (2001).
b. Jahan, A. and Chiang, J.Y.L. “Cytokine regulation of human sterol 12a-hydroxylase (CYP8B1) gene”. Am. J. Physiol. 288, G685-695 (2005).
c. Song, K. and Chiang, J.Y.L. “Glucagon and cAMP inhibit cholesterol 7a-hydroxylase (CYP7A1) gene expression in human hepatocytes: Discordant regulation of bile acid synthesis and gluconeogenesis”. Hepatology, 43, 117-125 (2006).
d. Li. T., A. Jahan, and J. Y.L. Chiang. Bile acids and cytokines inhibit the human cholesterol 7a-hydroxylase gene via the JNK/cJun pathway. Hepatology, 43:1202-1210 (2006).
Study of bile acid-activated cell signaling in regulation of bile acid synthesis. We studied bile acid-activated cell signaling in regulation of CYP7A1 gene and bile acid synthesis. We found that TGFβ1, TNFα, and insulin signaling cross talk to regulation CYP7A1 gene. Importantly, we found that human liver express FGF19, which might regulate CYP7A1 gene transcription by an autocrine/paracrine mechanism.
a. Song, K-H, E, Ellis, S. Strom and Chiang, J. Y. L. Hepatocyte growth factor inhibits cholesterol 7a hydroxylase expression in human hepatocytes, Hepatology, 46:1993-2002 (2007).
b. T. Li, and J.Y.L. Chiang. A novel role of transforming growth factors 1 in transcriptional repression of human cholesterol 7a-hydroxylase gene. Gastroenterology, 133:1660-1669 (2007).
c. T. Li, Ma, H and Chiang, J. Y. L. TGFβ1, TNFα, and insulin signaling crosstalk in regulation of the rat cholesterol 7a-hydroxylase gene expression. J. Lipid Res. 49:1981-1989, 2008.
d. Song, K.H., Li, T., Owsley, E., Strom, S. and J.Y.L. Chiang, J.Y.L. Bile acid activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7a-hydroxylase gene expression. Hepatology, 49:297-305. (2009).
Study the role of bile acid receptor and signaling in hepatic steatosis, insulin resistance and obesity. Our study showed that physiological concentrations of insulin stimulated CYP7A1 gene transcription and bile acid synthesis but non-physiological concentration found in insulin resistance strongly inhibited CYP7A1. Interestingly, high insulin and glucose strongly induced CYP7A1 expression and bile acid synthesis. CYP7A1 expression was reduced in fasting and rapidly induced upon feeding. In diabetic db/db and ob/ob mice CYP7a1 expression did not respond to fasting/refeeding, and basal bile acid levels were higher than non-diabetic mice. We generated CYP7A1 transgenic mice overexpressing CYP7A1. These mice were resistant to western high fat diet-induced fatty liver, insulin resistant and obesity. Interestingly, de novo cholesterol synthesis was markedly stimulated, but liver and serum cholesterol levels were normal. Thus increasing bile acid synthesis stimulated biliary cholesterol and bile acid secretion and maintained lipid homeostasis. We also reported that microRNA122 and mir33a were involved in regulation of CYP7A1 gene transcription.
a. Li, T, X. Kong, Owsley, E. Ellis, S. Strom, J. Y. L. Chiang. Insulin regulation of cholesterol 7a-hydroxylase expression in human hepatocytes: roles of forkhead box O1 and sterol regulatory element binding protein 1c. J. Biol. Chem. 281:28745-28754 (2006). PMC16885156.
b. Li, T., Owsley, E., Matozel, M., Hsu, P., Novak, C. M., and Chiang, J.Y.L. Transgenic expression of CYP7A1 in the liver prevents high fat diet-induced obesity and insulin resistance in mice. Hepatology 52:678-690, 2010. PMC3079544.
c. Li, T., Matozol, M., Boehme, S., Kong, B., Nilsson, L-M., Guo, G., and Chiang, J.Y.L. Overexpression of cholesterol 7a-hydroxylase promotes hepatic bile acid synthesis and secretion and maintains cholesterol homeostasis. Hepatology, 53:996-1006, 2011. PMC3079544
d. Li, T., Francl JM., Boehme, S., and Chiang, JYL. Regulation of cholesterol and bile acid homeostasis by the cholesterol 7α-hydroxylase/steroid response element-binding protein 2/microRNA-33a axis in mice. Hepatology, 58:1111-1121, 2013. PMC3735649
Ongoing Research Supports
R37DK58379-26 5/1/2011-4/30/2016 (MERIT Award, initial) 3.6CYM
Title: Regulation of Bile Acid Synthesis by nuclear receptor
The major goals of this project are to study nutrient regulation of CYP7A1 in bile acid synthesis and fatty liver diseases using FXR-/- and CYP7A-Tg mice and a humanized CYP7A1 mouse model. Current application is focused on the role of FXR and TGR5 signaling in regulation of CYP8B1 in dyslipidemia, high fat diet induced fatty liver and diabetes.
R01DK44442-18 6/01/2014 to 5/31/18 2.4CYM
Title: Molecular Biology of Bile Acid Synthesis
The major goals of this project are to study the mechanism of FXR and TGR5 signaling in bile acid metabolism, anti-inflammation in hepatocytes and nutrient regulation of circadian rhythm and fasting-restricted feeding on bile acid metabolism in NAFLD.
Complete list of Published Work on Pubmed: