Gut bile acids, Fxr, & Fgf15 in total parenteral nutrition-associated cholestasis

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DESCRIPTION (provided by applicant): Total parenteral nutrition (TPN) is widely used to supply nutrients to patients who cannot tolerate enteral feeding, including premature infants, patients with small-bowel surgery, or patients with pancreatic diseases. Long-term TPN is associated with a severe complication, TPN-associated cholestasis (TPN-AC). The mechanism underlying the cause of TPN-AC is poorly understood. Any effort to gain insight into the molecular mechanism of TPN-AC cause may allow us to develop a way to prevent its occurrence in future. Overt production of bile acids is toxic to livers and bile acid homeostasis needs to be tightly regulated. The most important mechanism is regulating bile acid homeostasis is medicated by a ligand-activated transcription factor belonging to the nuclear receptor superfamily, farnesoid X receptor (Fxr). We and others have shown that in mice, activation of intestinal Fxr induces fibroblast growth factor 15 (Fgf15) in the small intestine to suppress bile acid synthesis by inhibiting the gene expression of Cyp7a1 that encodes the rate-limiting enzyme in bile acid synthesis. In contrast, activation of Fxr in the liver induces small heterodimer partner (Shp), which only plays a minor role in inhibiting Cyp7a1 gene expression. This paradigm shift in understanding critical roles of gut factor-mediated regulation of bile acid synthesis in the liver has also been confirmed in human hepatocytes. Therefore, the intestinal bile acids/Fxr/Fgf15 pathway may be a fundamental basis for TPN-AC cause and treatment. The objective of this proposal is to determine the role of the intestinal bile acids/Fxr/Fgf15 pathway in TPN-AC development and treatment in mice, in order to provide a novel therapeutic strategy in humans. I hypothesize that the mechanism of TPN-AC cause is that increased bile acid synthesis and disruption of enterohepatic circulation by TPN leads to cholestasis, following loss of activation of the intestine bile acids/Fxr/Fgf15 pathway; re-establishing this pathway by replenishing bile acids into the gut, re-activation of intestinal Fxr or administering exogenous Fgf15 during TPN may prevent and/or treat TPN-AC. Three independent but inter-related aims are proposed to test this novel hypothesis in mice. Aim 1. Comprehensively characterize the disruption of bile acid homeostasis by TPN, determine the contribution of bile acid synthesis to TPN-AC development, and test whether replenishing gut bile acids prevent and/or treat TPN-AC. Aim 2. Determine the effects of TPN on intestinal Fxr function, and test to what degree re-activation of gut Fxr prevents or treats TPN-AC. Aim 3. Determine the role of Fgf15 in the prevention and treatment of TPN-AC. Our previous work has provided a paradigm shift in understanding the mechanism of suppressing bile acid synthesis in the liver by the gut bile acids/Fxr/Fgf15 pathway. This proposal, once completed, will provide a novel and critical scientific basis in understanding the mechanism(s) of TPN-AC cause, and likely have a huge impact on designing novel therapeutic strategies in future prevention and/or treatment of TPN-AC.