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Targeting Gut-Liver Signaling for the Treatment of Metabolic Disease
Matye, David
Matye, David
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Abstract
Bile acid synthesis occurs primarily in the liver and represents the major cholesterol catabolic pathway in humans. Bile acids are amphipathic molecules that aid in the digestion and absorption of fats and fat-soluble vitamins. Following their synthesis, bile acids are conjugated to amino acids taurine or glycine and stored in the gallbladder. After a meal, the gallbladder contracts, releasing its contents into the lumen of the proximal small intestine. In the ileum, bile acids are efficiently reabsorbed and recycled back to the liver through portal circulation. Bile acids are also signaling molecules and can activate both nuclear receptors and G-protein coupled receptors. Bile acid signaling regulates bile acid synthesis and transport as well as glucose, lipid, and amino acid metabolism. Maintenance of homeostasis of bile acid synthesis and circulation is essential for normal physiological function.Non-alcoholic fatty liver disease (NAFLD) is a progressive disease composed of a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Up to one-third of adults in the United States has NAFLD, which increases the risk of type 2 diabetes and cardiovascular disease, among others. Although NAFLD represents a significant health care burden, there are no approved therapeutics for its treatment. Bile acid targeted therapies have demonstrated efficacy against NAFLD in both experimental models and clinical trials. Agonism of the bile acid-activated nuclear receptor farnesoid X receptor (FXR) is currently the most advanced approach in the NAFLD therapeutic pipeline but produces undesirable side effects including pruritis and hypercholesteremia. Inhibition of bile acid reabsorption using bile acid binding resins or ASBT inhibitors is an effective therapeutic strategy to stimulate bile acid synthesis and reduce cholesterol. Although blocking gut bile acid reabsorption reduces FXR stimulation, it improves liver lipid content and insulin sensitivity in animal models of steatosis. The mechanisms by which interrupting intestinal bile acid recycling improves liver metabolic parameters are poorly understood. Additionally, the anti-fibrotic and anti-inflammatory effect in NASH models has not been previously characterized. Transcription factor EB (TFEB) regulates a network of genes involved in lysosome biogenesis and autophagy. TFEB activation is protective in models of NAFLD, and its inhibition may play a pathogenic role in disease progression. A recent study demonstrated that gut-liver bile acid signaling regulates TFEB nuclear translocation, and that inhibition of intestinal bile acid uptake promotes TFEB activation. This suggests that the lipid-lowering effects of ASBT inhibitors may be mediated in part through activation of TFEB. Although TFEB is known to promote mitochondrial biogenesis and lipophagy, the exact mechanisms by which TFEB prevents the development of NAFLD are unknown. The goal of these projects is to further the understanding of the mechanisms by which TFEB reduces liver lipid content. To this end, we employed global metabolomics using livers of mice with adenoviral-mediated hepatic TFEB overexpression. Furthermore, we aim to characterize the impact of blocking gut bile acid recycling on lipid accumulation, fibrosis, and inflammation in a mouse model of NASH. We fed mice a high fat, cholesterol, and fructose diet to induce NASH, and treated the animals with an ASBT inhibitor. We also used adeno-associated virus to overexpress FGF15 in the livers of these animals to gain further insight into the mechanisms by which bile acid signaling and metabolism impact NAFLD progression. Our studies revealed the novel finding that TFEB regulates sulfur amino acid metabolism to support fatty acid oxidation and metabolic flexibility. TFEB promotes cysteine availability through lysosomal proteolysis and enhanced synthesis from methionine, which promotes synthesis of coenzyme A and glutathione. Additionally, induction of hepatic steatosis by western diet feeding reduced liver cysteine, coenzyme A, and glutathione levels, which promoted hepatic metabolic dysfunction. Treating mice with an ASBT inhibitor moderately reduced liver injury in mice with early, but not late, stage NASH. Interestingly, co-treatment with an ASBT inhibitor and overexpression of FGF15 drastically improved liver fibrosis, injury, and inflammation and promoted weight loss through intestinal lipid malabsorption. These findings offer insight into the pathogenesis of NAFLD and mechanisms by which TFEB reduces hepatic lipid accumulation. Additionally, our results provide rationale and understanding of the potential clinical utility of bile acid targeted therapies in combination for the treatment of NAFLD and obesity.
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2022-01-01
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University of Kansas
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Keywords
Pharmacology, Bile acid, Liver, NAFLD, NASH, Non-alcoholic fatty liver disease, Steatosis