Nonalcoholic fatty liver disease (NAFLD) is an alarming public health concern and now considered the most common liver disease in the Western world. Patients with NAFLD may develop nonalcoholic steatohepatitis (NASH) of which many develop hepatic injury that may progress to cirrhosis. We have previously shown that in chronic cholestatic liver diseases, cholangiocytes, through the products of their cellular activation such as secretin (SCT), are the key link between bile duct injury and the subepithelial fibrosis that characterizes chronic hepatobiliary injury. We have also demonstrated that activation of the SCT/SR axis plays a key role in the progression of liver fibrosis and biliary damage during cholestasis in animal models and human liver samples via secretion of transforming growth factor-b1 (TGF-b1) by cholangiocytes and subsequent activation of hepatic stellate cells (HSCs). Recent evidence and our novel preliminary data indicate that cholangiocytes play a key role in the pathogenesis of NAFLD/NASH through activation of biliary damage/proliferation and subsequent liver fibrosis. Our preliminary data that the SCT/secretin receptor (SR) axis is upregulated in cholangiocytes in an animal model of NAFLD/NASH and human liver samples with steatosis and steatohepatitis support the concept that the SCT/SR axis plays a key role in the progression of NAFLD and NASH. Based upon these findings, we propose the central hypothesis that the SCT/SR axis signaling is key for mediating the proliferative and activated profibrogenic biliary phenotype that contributes to the progression of hepatic steatosis and fibrosis during the pathogenesis of NAFLD/NASH. To test our hypothesis, two Specific Aims are proposed: (i) activation of the SCT/SR axis stimulates a neuroendocrine/profibrogenic biliary phenotype in response to FFA-induced biliary damage triggering the activation of HSCs via a paracrine TGF-b1-dependent mechanism; and (ii) inhibition of the SCT/SR axis and downstream pathways attenuates the activated neuroendocrine/profibrogenic biliary phenotype and hepatic steatosis and fibrosis during the progression of NAFLD/NASH. Completion of the proposed studies will provide a translational mechanism of how activation of the SCT/SR axis promotes local and systemic responses to mediate activation of neuroendocrine/profibrogenic biliary phenotype and hepatobiliary steatosis and fibrosis during the progression of NAFLD/NASH.!

Public Health Relevance

The health relatedness of this grant proposal is that effective treatments are lacking for patients with NAFLD and NASH. NAFLD is a leading cause of chronic liver disease in the U.S. Chronic cholestatic liver diseases cause proliferation/damage of bile ducts in the liver. Management of the chronic liver diseases, NAFLD and NASH, represents one of the major challenges for the Veterans Administration. The current studies that are proposed will provide insight into the key role of cholangiocytes in the pathogenesis of NAFLD/NASH and the development of novel therapeutic approaches for NAFLD/NASH.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000574-11
Application #
9896734
Study Section
Gastroenterology (GAST)
Project Start
2009-10-01
Project End
2022-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
11
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Rlr VA Medical Center
Department
Type
DUNS #
608434697
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Ehrlich, Laurent; Scrushy, Marinda; Meng, Fanyin et al. (2018) Biliary epithelium: A neuroendocrine compartment in cholestatic liver disease. Clin Res Hepatol Gastroenterol 42:296-305
Lewis, Phillip L; Su, Jimmy; Yan, Ming et al. (2018) Complex bile duct network formation within liver decellularized extracellular matrix hydrogels. Sci Rep 8:12220
Stephenson, Kristen; Kennedy, Lindsey; Hargrove, Laura et al. (2018) Updates on Dietary Models of Nonalcoholic Fatty Liver Disease: Current Studies and Insights. Gene Expr 18:5-17
Sato, Keisaku; Meng, Fanyin; Giang, Thao et al. (2018) Mechanisms of cholangiocyte responses to injury. Biochim Biophys Acta Mol Basis Dis 1864:1262-1269
Luo, Xianjun; Li, Honggui; Ma, Linqiang et al. (2018) Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice. Gastroenterology 155:1971-1984.e4
Francis, Heather; Kennedy, Lindsey; Alpini, Gianfranco (2018) Dual ablation of ?- and ?-catenin: Critical regulators of junctions and their functions. Hepatology 67:2079-2081
Zhou, Tianhao; Wu, Nan; Meng, Fanyin et al. (2018) Knockout of secretin receptor reduces biliary damage and liver fibrosis in Mdr2-/- mice by diminishing senescence of cholangiocytes. Lab Invest 98:1449-1464
Meng, Fanyin; Kennedy, Lindsey; Hargrove, Laura et al. (2018) Ursodeoxycholate inhibits mast cell activation and reverses biliary injury and fibrosis in Mdr2-/- mice and human primary sclerosing cholangitis. Lab Invest 98:1465-1477
Kennedy, Lindsey; Hargrove, Laura; Demieville, Jennifer et al. (2018) Knockout of l-Histidine Decarboxylase Prevents Cholangiocyte Damage and Hepatic Fibrosis in Mice Subjected to High-Fat Diet Feeding via Disrupted Histamine/Leptin Signaling. Am J Pathol 188:600-615
Kennedy, Indsey; Francis, Heather; Meng, Fanyin et al. (2017) Diagnostic and therapeutic potentials of microRNAs in cholangiopathies. Liver Res 1:34-41

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