Type 2 diabetes and obesity is associated with dyslipidemia, hyperglycemia and insulin resistance. Hepatic steatosis contributes to insulin resistance and non-alcoholic fatty liver disease. Bile acids play a key role in regulation of lipid, glucose and energy metabolism by activating a nuclear hormone receptor FXR, and G protein-coupled receptor TGR5. Our central hypothesis is that nutrients, growth hormone, circadian rhythm and gut microbiota regulate bile acid synthesis to maintain metabolic homeostasis, and impairment of this regulatory response contributes to dyslipidemia, glucose intolerance, insulin resistance, fatty liver disease and obesity.
Specific aim 1 will study the role of bile acid receptor signaling in regulation of hepatic metabolism. The mechanism of growth hormone-STAT5 regulation of bile acid synthesis and a male predominant Cyp7b1 will be studied using reporter assay and chromatin immuno- precipitation assay to identify STAT5 binding sites and epigenetic regulation of Cyp7b1 promoter by STAT5. Tgr5-/-, Cyp7a1-/- and adenovirus-Cyp8b1 over-expressed mice with different bile acid composition and Cyp7a1, Cyp8b1 and cyp7b1 expression will be used to study growth hormone regulation.
Specific aim 2 will study the role of bile acid receptor signaling in fatty liver, insulin resistance and diabetes. The mechanism of FXR and TGR5 in GLP-1 secretion and glucose metabolism will be studied. Tgr5-/- mice will be used to study effect of vertical sleeve gastrectomy on improving insulin resistance, dyslipidemia and microbiome before and after surgery.
Specific aim 3 will study circadian rhythm of bile acid synthesis in metabolic homeostasis. The liver-gut microbiota axis plays a critical role in bile acid metabolism and disturbance of circadian rhythm is linked to metabolic diseases. Dysbiosis is associated with obesity, and inflammatory bowel diseases. Tgr5-/-, FXR-/- and Cyp7a1-/- with different bile acid pool size and/or composition will be used for time-restricted feeding of Western high fat/high cholesterol diet to study bile acid metabolism and gut microbiome by RNA sequencing. Cyp7a1-/-, Fxr-/-, and Tgr5-/- will be used to determine how time-restricted feeding in day time or night time affect affect hepatic gene rhythms and overall bile acid homeostasis.
Understanding the underlying molecular mechanism of bile acid signaling in liver metabolism and inflammation is critical for developing bile acid-based therapeutic drugs for treating metabolic liver diseases. Study liver to gut axis and circadian disruption on gut microbiome and bile acid metabolism, and the role of TGR5 signaling on diabetes remission after gastric bypass is highly relevant to liver diseases and treatment.
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