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.
- PhD, Kent State University, Ohio, US
- Postdoc, Northeast Ohio Medical University, Ohio, US
- Cholesterol and bile acid signaling in metabolic diseases
- Regulation of insulin sensitivity in Type-II diabetes
- Mechanisms of liver injury
1 R01 DK117965-01A1 (2/5/2019 – 11/30/2023)
Title: Regulation of bile acid metabolism and signaling in metabolic diseases.
Major goals: This project investigates a crosstalk of bile acid signaling and TFEB in the regulation of metabolic homeostasis in diabetes and NAFLD.
1R01DK131064-01 (1/1/2022 -12/31/2025)
Title: Sulfur Amino Acid Metabolism and Regulation of Hepatic Metabolic Flexibility
Major goals: This project investigates the role and regulation of hepatic sulfur amino acid metabolism in the pathogenesis of metabolic and inflammatory liver disease
1R01DK128416-01A1 (9/30/2021-7/31/2025)Maternal Obesity and Pediatric NAFLD: Fetal Origins and Long-term outcomes in Non-Human Primates
Role: Co-I (PI: Jacob E. Friedman, OUHSC)
R01DK121497-01A1 (07/01/2019 - 06/30/2023)
Aerobic Fitness, Mitochondrial Function, and Fatty Liver Disease
Role: Co-I (PI: Thyfault, John P, KUMC)
Major Goals: The goal of this grant is to examine mechanisms by which aerobic fitness impacts susceptibility for fatty liver through modulating hepatic mitochondrial function, bile acid metabolism, and epigenetic programming.
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 (2022). TFEB regulates sulfur amino acid and coenzyme A metabolism to support hepatic metabolic adaptation and redox homeostasis. Nature Communications, 13(1), 5696. PMID: 36171419. DOI: 10.1038/s41467-022-33465-9
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 U S A. 2022 Feb 8;119(6): e2111737119. PMID: 35115401
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 improve therapeutic efficacy in experimental non-alcoholic steatohepatitis. Cellular and Molecular Gastroenterology and Hepatology (2021) April 26. PMID: 33965587
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.
Cheng Chen, Jibiao Li, David Matye, Yifeng Wang, Tiangang Li. Hepatocyte Sortilin 1 knockout and treatment with a Sortilin 1 inhibitor reduced plasma cholesterol in Western diet-fed mice. J Lipid Res. (2019) Mar; 60(3):539-549. PMID: 30670473
Yifeng Wang, Jibiao Li, David Matye, Yuxia Zhang, Katie Dennis, Wen-Xing Ding, Tiangang Li. Bile acids regulate cysteine catabolism and glutathione regeneration to modulate hepatic sensitivity to oxidative injury. (2018) JCI Insight. 3(8). PMID: 29669937; PMCID: PMC5931126
Jibiao Li, Yifeng Wang, David J. Matye, Hemantkumar Chavan, Partha Krishnamurthy, Feng Li, Tiangang Li. Sortilin 1 modulates hepatic cholesterol lipotoxicity in mice via functional interaction with liver carboxylesterase 1. J Biol Chem. (2017) 292(1):146-160. PMID: 27881673; PMCID: PMC5217674 (Selected article in the Special Issue: Diabetes, obesity and the metabolic syndrome by JBC, Sept 2019)
Yifeng Wang, Yifeng Ding, Jibiao Li, Hemantkumar Chavan, David Matye, Hong-Min Ni, John YL. Chiang, Partha Krishnamurthy, Wen-Xing Ding, Tiangang Li. Targeting the enterohepatic bile acid signaling induces hepatic autophagy via a CYP7A1 - AKT - mTOR axis in mice. Cell Mol Gastroenterol Hepatol. (2016) 3(2):245-260. PMID: 28275691; PMCID: PMC5331786 (Selected as the Cover story)
Link to Li Publications: https://www.ncbi.nlm.nih.gov/myncbi/tiangang.li.1/bibliography/public/