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.

Public Health Relevance

The survival of patients who cannot tolerate enteral feeding, such as premature infants, patients undergone small-bowel surgery, or patients with pancreatic diseases, can be greatly improved by total parenteral nutrition (TPN). Long-term TPN is associated with severe complications, such as TPN-associated cholestasis (TPN- AC). The mechanism underlying TPN-AC development is poorly understood. Understanding the molecular mechanism of TPN-AC will have a huge impact on the future prevention and/or treatment of TPN-AC in the clinic.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM104037-02
Application #
8697069
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Somers, Scott D
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Zhu, Yan; Liu, Hongxia; Zhang, Min et al. (2016) Fatty liver diseases, bile acids, and FXR. Acta Pharm Sin B 6:409-412
Moscovitz, Jamie E; Kong, Bo; Buckley, Kyle et al. (2016) Restoration of enterohepatic bile acid pathways in pregnant mice following short term activation of Fxr by GW4064. Toxicol Appl Pharmacol 310:60-67
Schumacher, Justin D; Guo, Grace L (2016) Regulation of Hepatic Stellate Cells and Fibrogenesis by Fibroblast Growth Factors. Biomed Res Int 2016:8323747
Zhan, Le; Yang, Ill; Kong, Bo et al. (2016) Dysregulation of bile acid homeostasis in parenteral nutrition mouse model. Am J Physiol Gastrointest Liver Physiol 310:G93-G102
Kong, Bo; Zhu, Yan; Li, Guodong et al. (2016) Mice with hepatocyte-specific FXR deficiency are resistant to spontaneous but susceptible to cholic acid-induced hepatocarcinogenesis. Am J Physiol Gastrointest Liver Physiol 310:G295-302
Baker, Angela A; Guo, Grace L; Aleksunes, Lauren M et al. (2015) Isoform-Specific Regulation of Mouse Carboxylesterase Expression and Activity by Prototypical Transcriptional Activators. J Biochem Mol Toxicol 29:545-51
Li, Guodong; L Guo, Grace (2015) Farnesoid X receptor, the bile acid sensing nuclear receptor, in liver regeneration. Acta Pharm Sin B 5:93-8
Schumacher, Justin D; Guo, Grace L (2015) Mechanistic review of drug-induced steatohepatitis. Toxicol Appl Pharmacol 289:40-7
Cheng, Qiuqiong; Inaba, Yuka; Lu, Peipei et al. (2015) Chronic activation of FXR in transgenic mice caused perinatal toxicity and sensitized mice to cholesterol toxicity. Mol Endocrinol 29:571-82
Schmitt, Johannes; Kong, Bo; Stieger, Bruno et al. (2015) Protective effects of farnesoid X receptor (FXR) on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal. Liver Int 35:1133-44

Showing the most recent 10 out of 22 publications