Ph.D., Kent State University, 2006
About a third of adults and increasing number of children in developed countries are affected by non-alcoholic fatty liver disease (NAFLD). NAFLD is closely associated with over-nutrition, central obesity and insulin resistance, which directly contributes to hepatic triglyceride accumulation, diabetic dyslipidemia and increased risk of cardiovascular diseases.
Sortilin 1 is a multi-ligand trans-membrane receptor localized in trans-Golgi network and early endosome and has been shown to assist in sorting various functionally-unrelated target proteins in the secretory or endosomal pathways. Numerous recent genome-wide association studies (GWAS) identified that Sort1 showed the strongest association with serum cholesterol, serum triglyceride and cardiovascular disease risk in humans, supporting that Sort1 is a novel regulator of lipid metabolism and its function is closely linked to human diseases. Therefore the overall goal of my research is to obtain new insights on the effects and mechanisms of Sort1 regulation of liver metabolism and its role in the pathogenesis of metabolic disorders.
My current study is concerned with Sort1 regulation of triglyceride and cholesterol metabolism in the liver and circulation. Our results showed that liver Sort1 is consistently and markedly lower in various mouse models of hepatic steatosis and diabetes, while increasing Sort1 expression specifically in the liver simultaneously lowered serum triglyceride and cholesterol. As such, one area of my research will use in vivo mouse models with adenovirus-mediated liver-specific Sort1 gain- and loss-of-function and tissue-specific Sort1 transgenic mice to define the effects and mechanisms of liver Sort1 in regulating hepatic and peripheral lipid metabolism, secretion and uptake. The mechanism of Sort1 regulation of lipid metabolism at the cellular levels will be investigated by using molecular, physiological and imaging approaches in primary hepatocyte systems. Another focus of my research is on understanding how cellular signaling pathways (insulin, inflammation, bile acids) and nuclear receptors regulate Sort1 at transcription and posttranslational levels. These Sort1 regulatory mechanisms could underlie the physiological function of liver Sort1, the molecular basis for impaired hepatic Sort1 function in diseased states, and the potential modulation of Sort1 function by therapeutic approaches.
Tiangang Li, Jessica M. Francl, Shannon Boehme, Adrian Ochoa, Youcai Zhang, Curtis D. Klaassen, Sandra K. Erickson, and John Y. L. Chiang. Glucose and Insulin Induction of Bile Acid Synthesis: Mechanisms and Implication in Diabetes and Obesity. J. Biol. Chem, 13;287(3):1861-73. (2012) PMID:22144677
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, Mar;53(3):996-1006 (2011) PMID: 21319191
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, Aug;52(2):678-90 (2010) PMID: 20623580
Tiangang Li and John Chiang A Novel Role of Transforming Growth Factor beta1 in Transcriptional Repression of Human Cholesterol 7alpha-Hydroxylase Gene. Gastroenterology, 133(5):1660-9 (2007) PMID: 17920062
Tiangang Li and John Y.L. Chiang. Rifampicin Induction of CYP3A4 Requires PXR Cross-talk with HNF4α and Co-activators, and Suppression of SHP Gene Expression. Drug Metab. Dispos. 34(5): 756-64 (2006) PMID: 16455805
Tiangang Li, Asmeen Jahan and John Y.L. Chiang. Bile Acids and Cytokines Inhibit the Human cholesterol 7α-hydroxylase Gene Via the JNK/cJun Pathway in Human Liver Cells. Hepatology, 43:1202-1210 (2006) PMID: 16729332
Tiangang Li, Xiaoying Kong, Erika Owsley, Ewa Ellis, Stephan Strom and John Y.L. Chiang. Insulin Regulation of Cholesterol 7alpha-hydroxylase expression in Human Hepatocytes: Roles of Forkhead transcription Factor (FoxO1) and Sterol Regulatory Element Binding Protein 1c (SREBP-1c), J. Biol. Chem. 29;281 (39) :28745-54 (2006) PMID: 16885156Tiangang Li and John Y.L. Chiang. Mechanism of Rifampicin and Pregnane X Receptor (PXR) Inhibition of Human Cholesterol 7α-hydroxylase Gene (CYP7A1) Transcription. Am J Physiol Gastrointest Liver Physiol. 288:G74-G84 (2005) PMID: 15331348