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:
- Bile acid signaling crosstalk with Transcriptional Factor EB (TFEB), a nutrient sensing master regulator of lysosomal biogenesis and autophagy, in the regulation of cholesterol and bile acid metabolism.
- Bile acid regulation of amino acid metabolism in control of hepatic glucose metabolism, insulin sensitivity and obesity development.
- Pharmacological modulation of hepatic insulin resistance in fatty liver disease.
- Bile acid signaling in aging-associated hepatic oxidative stress and drug-induced liver injury.
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.
Tiangang Li, Erika Owsley, Michelle Matozel, Peter Hsu, and John Y.L. Chiang. Transgenic expression of CYP7A1 in the liver prevents high fat diet-induced obesity and insulin resistance in mice. Hepatology. (2010) 52(2):678-90. PMID: 20623580
Tiangang Li, Michelle Matozel, Shannon Boehme, Bo Kong, Lisa-Mari Nilsson, Grace Guo, Ewa Ellis, and John Y. L. Chiang. Cholesterol 7α-hydroxylase promotes hepatic cholesterol and bile acid synthesis and secretion and maintains cholesterol homeostasis. Hepatology. (2011) 53(3):996-1006. PMID: 21319191
Tiangang Li, Jessica M. Francl, Shannon Boehme, and John Y. L. Chiang. Regulation of cholesterol and bile acid homeostasis by the CYP7A1/SREBP2/miR-33a axis. Hepatology. (2013) 58(3):1111-21. PMID: 23536474
Shuangwei Li, Diane D.F. Hsu, Bing Li, Xiaolin Luo, Nazilla Alderson, Liping Qiao, Lina Ma, Helen H. Zhu, Zhao He, Kelly Suino-Powell, Kaihong Ji, Jiefu Li, Jianhua Shao, H. Eric Xu, Tiangang Li and Gen-Sheng Feng. Cytoplasmic Tyrosine Phosphatase Shp2 Coordinates Hepatic Regulation of Bile Acid and FGF15/19 Signaling to Repress Bile Acid Synthesis. Cell Metabolism (2014) 20(2):320-32. PMID: 24981838; PMCID: PMC4365973
Tiangang Li, John YL Chiang. Bile acid signaling in metabolic diseases and drug therapies Pharmacol Rev. (2014) 66(4):948-83 PMID: 25073467; PMCID: PMC4180336
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)
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, Wen-Xing Ding and Tiangang Li. Cholesterol and Bile Acid -Mediated Regulation of Autophagy in Fatty Liver Diseases and Atherosclerosis. Biochim Biophys Acta. (2018) 1863(7):726-733. PMID: 29653253; PMCID: PMC6037329 (This article is selected to be included in: “BBA Collection: Programmed Cell Death”, March 2019)
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
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, Sumedha Gunewardena, Feng Li, David 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. Nat Commun. 2020 Jul 17;11(1):3612. doi: 10.1038/s41467-020-17363-6.PMID: 32681035