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The Metabolic Impact of the Gut-Liver Bile Acid Signaling in Metabolic and Inflammatory Liver Disease
Wang, Yifeng
Wang, Yifeng
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Abstract
Bile acids are synthesized from cholesterol in hepatocytes and secreted into bile. After a meal, bile acids are released from the gallbladder into the small intestine to facilitate the digestion and absorption of dietary fats and lipid soluble vitamins. Most bile acids in the intestine are re-absorbed in the terminal ileum and transported back to the liver via the portal circulation. Bile acids circulating in the enterohepatic circulation play important roles in maintaining bile acid, lipid and glucose homeostasis and inflammatory response. Disruption of bile acid homeostasis could contribute to various liver diseases and metabolic disorders. Therapeutic approaches targeting bile acid signaling have been developed for the treatment of nonalcoholic fatty liver disease (NAFLD). Bile acid receptor Farnesoid X receptor (FXR) agonists have been shown to ameliorate steatosis and liver damage and improve insulin resistance in NASH patients but also cause adverse effects including gastrointestinal disturbances, hypercholesterolemia and pruritus. A better understanding of the global metabolic effect of gut-liver bile acid signaling would contribute to the development of more efficient bile acid signaling-based therapies for metabolic disease. Recent studies showed that blocking intestinal bile acid re-uptake improved lipid homeostasis and insulin sensitivity in diabetic animal models and human patients, suggesting that inhibiting intestinal bile acid absorption may represent a novel approach to treat metabolic disease. However, the underlying mechanisms are still incompletely understood. The goal of my research is to understand the effects and mechanisms by which blocking intestinal bile acid re-uptake impacts hepatic metabolic pathways. To achieve this goal, I used bile acid sequestrant cholestyramine-treated mice and intestine-restricted apical sodium-dependent bile salt transporter (ASBT) inhibitor-treated mice as experimental models and studied the effects on metabolic pathways in the liver and the underlying mechanisms. The effect of blocking intestinal bile acid uptake on hepatic metabolic pathways and the underlying mechanisms were investigated with comprehensive physiological and molecular approaches and unbiased metabolomics analysis. My study has revealed that the gut-liver bile acid signaling inhibits hepatic autophagy flux and transcriptional factor EB (TFEB), a master stimulator of lysosomal biogenesis. Increased hepatic TFEB function promoted bile acid synthesis and prevented hepatic cholesterol and triglyceride accumulation in response to Western diet challenges. Pharmacologically targeting intestinal bile acid uptake may activate autophagy flux and TFEB function to ameliorate hepatic steatosis and inflammatory responses and improving insulin sensitivity in Western diet-fed mice. However, my study also found that blocking the gut-liver bile acid signaling axis may disrupt hepatic cysteine and glutathione homeostasis. Impaired hepatic glutathione regeneration may represent an undesirable effect of increased susceptibility to oxidative injury in certain pathological conditions. In summary, findings from my study yielded novel insights of how gut-liver signaling regulates the complex hepatic metabolic pathways and how targeting the gut-liver signaling axis could improve hepatic metabolic homeostasis in NAFLD. New knowledge on the pathophysiological function of bile acids may help establish the molecular basis for developing effective and safer bile acid-based therapies for metabolic diseases.
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2019-01-01
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University of Kansas
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This item contains archived web content.
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- Embargoed until 2169-05-31
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Keywords
Toxicology, Autophagy, Bile acid, FXR, Glutathione, Metabolic disease, TFEB