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John Y. L. Chiang, Ph.D. Lab

Bio

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John Y. L. Chiang, Ph.D., Distinguished University Professor of Biochemistry/Molecular Pathology

Research Interests

 
Dr. Chiang’s research is focused on studying bile acid and cholesterol metabolism in the liver and the role of bile acids and nuclear receptors in regulation of glucose, lipid and energy metabolism in liver diseases, diabetes and obesity. This laboratory first purified cholesterol 7α-hydroxylase (CYP7A1), a microsomal cytochrome P450 with strict substrate specificity for cholesterol, and cloned the gene CYP7A1. CYP7A1 is the first and rate-limiting enzyme in the classic bile acid biosynthetic pathway that converts cholesterol to bile acids.


Chiang Lab Photo 1
Pictured L-R: Adrian Ochoa, medical student; Preeti Pathak, Ph.D.,Postdoctoral Fellow; John Y. L. Chiang, Ph.D., Distinguished University Professor of Biochemistry/Molecular Pathology; Shannon Boehme, Lab Manager; Tiangang Li, Ph.D., Research Assistant Professor; Jessica Ferrell, Ph.D., Research Assistant Professor.

Bile acids are physiological detergents that are required for intestinal absorption and transport of nutrient, fats, steroids, and drugs. Bile acids are the end products of cholesterol catabolism in the liver. Bile acids undergo enterohepatic recirculation back to the liver to inhibit bile acid synthesis and CYP7A1 gene transcription. Bile acids are endogenous ligands of a bile acid receptor FXR, which regulates lipid and glucose metabolism, and the xenobiotic receptors, PXR and CAR, and VDR, which induce phase I drug metabolizing CYP enzymes, phase II drug conjugating enzymes and phase III drug transporters in liver and intestines.


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John Y. L. Chiang, Ph.D., Distinguished University Professor of Biochemistry/Molecular Pathology

Dr. Chiang has been studying the molecular mechanisms of transcriptional regulation of the CYP7A1 gene. His laboratory is the first to identify a bile acid response element in the CYP7A1 gene promoter that contains several several hormone response elements, which are putative binding site for nuclear receptors such as HNF4, LXR, and LRH. It is thought that FXR induces a negative nuclear receptor SHP, which inhibits the transcriptional activity of HNF4 and LRH, and results in inhibiting CYP7A1 gene transcription. In the intestine, bile acid-activated FXR induces FGF15/19, which may be transported to the liver to activate a membrane FGFR4 receptor signaling to inhibit CYP7A1.


Chiang Lab Photo 2
Pictured L-R: Shannon Boehme, Lab Manager; John Y. L. Chiang, Ph.D., Distinguished University Professor of Biochemistry/Molecular Pathology; Preeti Pathak, Ph.D., Postdoctoral Fellow; Tiangang Li, Ph.D., Research Assistant Professor; Jessica Ferrell, Ph.D., Research Assistant Professor; Adrian Ochoa, medical student.

Dr. Chiang’s research also studies FXR-independent bile acid signaling in activation of several signal transduction pathways including MAPK, TGFβ, TNFα, HGF, FGF19/FGFR4, insulin and VDR. These signaling pathways play critical roles in cell growth and differentiation, drug metabolism, inflammation, cell proliferation, cell death and liver injury. Bile acids play a key role in maintaining metabolic homeostasis in the liver. Bile acid signaling regulates lipids, glucose, and energy homeostasis via bile acid-activated nuclear receptors. Bile acids also activate a membrane G protein-coupled receptor TGR5 in brown adipose tissue and induce deiodinase 2, which convertsT4 to T3 and stimulate energy metabolism.


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John Y. L. Chiang, Ph.D., Distinguished University Professor of Biochemistry/Molecular Pathology

More recently, Dr. Chiang’s laboratory has generated transgenic mice that overexpress CYP7A1. These mice have enlarged bile acid pool and more hydrophoblic bile acid composition, and are resistant to Western high fat diet-induced insulin resistance and obesity. This study demonstrates that increased bile acid pool may reduce serum triglyceride, increase insulin sensitivity and energy metabolism to reduce weight. These mice are being crossed to Fxr and Shp knockout mice to study FXR-independent bile acid signaling in liver metabolism. His laboratory also created humanized CYP7A1 mice, which carry a human CYP7A1 BAC clone in Cyp7a1 knockout background. This mouse model will be used as an in vivo model to study molecular mechanism of human CYP7A1 gene transcription.


Chiang Lab Photo 3
Pictured L-R:  John Y. L. Chiang, Ph.D., Distinguished Professor of Biochemistry/Molecular Pathology; Preeti Pathak, Ph.D., Postdoctoral Fellow; Tiangang Li, Ph.D., Research Assistant Professor; Jessica Ferrell, Ph.D., Research Assistant Professor; Adrian Ochoa, medical student.

More recent study in Dr. Chiang’s laboratory shows that glucose is a physiological activator of CYP7A1 gene transcription. Glucose and insulin signaling activates CYP7A1 gene transcription by increasing Histone acetylation and decreasing Histone methylation. This epigenetic mechanism may rapidly stimulate bile acid synthesis during postprandial state to maintain lipid and energy homeostasis. In both type-1 and type-2 diabetes, bile acid synthesis and pool size are increased and glucose/insulin does not further increase bile acid synthesis, suggesting that bile acid metabolism is dysregulated in diabetes.


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John Y. L. Chiang, Ph.D., Distinguished University Professor of Biochemistry/Molecular Pathology

Bile acids and derivatives are being used for treatment of gallstone and digestive diseases, diabetes and obesity.


Chiang Lab Photo 4
Pictured L-R: Adrian Ochoa, medical student; Preeti Pathak, Ph.D., Postdoctoral Fellow; John Y. L. Chiang, Ph.D., Distinguished University Professor of Biochemistry/Molecular Pathology; Shannon Boehme, Lab Manager; Tiangang Li, Ph.D., Research Assistant Professor; Jessica Ferrell, Ph.D., Research Assistant Professor.