Diabetes and non-alcoholic fatty liver disease (NAFLD) are closely associated with hepatic fat and cholesterol accumulation, hepatocyte organelle dysfunction, low grade inflammation, and dyslipidemia. Patients with diabetes and NAFLD have significantly higher risk of cardiovascular disease, which remains the leading cause of death worldwide. Bile acids are synthesized from cholesterol only in the liver. Hepatic bile acid synthesis is the only major cholesterol catabolic elimination mechanism in the body, and bile acids act as physiological detergents to facilitate dietary lipid and fat-soluble vitamin absorption in the small intestine. Furthermore, bile acids are signaling molecules that critically regulate metabolic homeostasis and inflammatory response by activating nuclear receptors and intracellular signaling pathways. Different therapeutic approaches targeting the bile acid signaling pathways have shown great promise for treating metabolic and chronic liver diseases including cholestasis, dyslipidemia, diabetes, and fatty liver disease. A major focus of the lab is to investigate how modulating the enterohepatic bile acid signaling impacts the complex metabolic network via distinct mechanism of actions. Through these studies, we hope to better understand the pathophysiological function of bile acids and to help establish the molecular basis for developing effective bile acid-based therapies. Current ongoing projects include:
We address these questions by employing experimental mouse models through viral vector-mediated liver-specific gene delivery, tissue-specific genetic knockout, and pharmacological treatment approaches and a combination of physiological, molecular cell biology techniques and unbiased transcriptomics and metabolomics approaches.
Education:
1999 B.S. Jilin University, China
2006 PhD Kent State University, USA
Clinical/Research Interests:
- Cholesterol and bile acid signaling in metabolic diseases
- Regulation of insulin sensitivity in Type-II diabetes
- Mechanisms of liver injury
Funding:
1R01 DK117965 (2/5/2019 – 4/30/2030) Title: Regulation of bile acid metabolism and signaling in metabolic diseases. Role: PI. Goal: To investigate Gly-MCA as a novel agent to treat hepatobiliary injury in cholestasis
1R01DK131064 (1/1/2022 -12/31/2025) Title: Sulfur Amino Acid Metabolism and Regulation of Hepatic Metabolic Flexibility. Role: PI. Goal: to investigate pathways controlling hepatic sulfur amino acid metabolism and their impact on the development of fatty liver disease.
1R01DK134316 (2/16/2023 – 1/31/2027) Title: Novel Roles of Cullin-RING E3 Ligases in Liver Pathophysiology. Role: PI. Goal: To investigate the role of Cullin-RING E3 ligase in regulating hepatic insulin sensitivity.
Select Publications:
Selected Publications:
- Yifeng Wang, Sumedha Gunewardena, Feng Li, David J. Matye, Cheng Chen, Xiaojuan Chao, Taeyoon Jung, Yuxia Zhang, Maciej Czerwiński, Hong-Min Ni, Wen-Xing Ding, Tiangang Li. An FGF15/19-TFEB regulatory loop controls hepatic cholesterol and bile acid homeostasis Nature Communications (2020) Jul 17;11(1):3612. PMID: 32681035; PMCID: PMC7368063.
- David J. Matye, Huaiwen Wang, Wenyi Luo, Rachel R. Sharp, Cheng Chen, Lijie Gu, Kenneth L. Jones, Wen-Xing Ding, Jacob E. Friedman, Tiangang Li. Combined ASBT inhibitor and FGF15 treatment improves therapeutic efficacy in experimental non-alcoholic steatohepatitis. Cellular and Molecular Gastroenterology and Hepatology (2021) 12(3):1001-1019 PMID:33965587
- Cheng Chen, Lijie Gu, David J. Matye, Yung-Dai Clayton, Mohammad Nazmul Hasan, Yifeng Wang, Jacob E. Friedman, Tiangang Li. Cullin neddylation inhibitor attenuates hyperglycemia by enhancing hepatic insulin signaling through insulin receptor substrate stabilization. Proc. Natl. Acad. Sci. USA. (2022) Feb 8;119(6): e2111737119. PMID: 35115401. PMCID: PMC8832973
- David Matye, Sumedha Gunewardena, Jianglei Chen, Huaiwen Wang, Yifeng Wang, Mohammad Nazmul Hasan, Lijie Gu, Yung Dai Clayton, Yanhong Du, Cheng Chen, Jacob E. Friedman, Shelly C. Lu, Wen-Xing Ding, Tiangang Li. TFEB regulates sulfur amino acid and coenzyme A metabolism to support hepatic metabolic adaptation and redox homeostasis. Nature Communications (2022) 13(1), 5696. PMID: 36171419. PMCID: PMC9519740.
- Lijie Gu, Yanhong Du, Jianglei Chen, Mohammad Nazmul Hasan, Yung Dai Clayton, David Matye, Jacob E. Friedman, Tiangang Li. Cullin 3 RING E3 ligase inactivation causes NRF2-dependent NADH reductive stress, hepatic lipodystrophy, and systemic insulin resistance. Proc. Natl. Acad. Sci. USA. (2024) Apr 17;121(17): e2320934121. PMCID: PMC11046679. PMID: 38630726
Link to full publication list: http://www.ncbi.nlm.nih.gov/sites/myncbi/tiangang.li.1/bibliography/47215534/public/?sort=date&direction=ascending