Cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis are often associated with increased serum bile acid concentrations. Previous reports have also indicated a decrease in circulating glucocorticoid levels in these diseases. Glucocorticoid production and secretion are under the direct control of the hypothalamus-pituitary-adrenal (HPA) axis. We have obtained novel preliminary data indicating that there is a dampening of the HPA axis activity in our rodent model of cholestatis liver disease and that this may contribute to the cholangiocyte outgrowth seen in the early stages of cholestasis. The overall objective of this proposal is to determine the consequences of cholestatic liver disease on the brain and more specifically on the HPA axis and in turn determine the subsequent effects of a dampened HPA axis activity have on cholangiocyte proliferation. Based upon strong preliminary data, we propose the novel central hypothesis that the bile acids that accumulate in the serum during cholestasis are responsible for the dampening of the HPA axis and that the subsequent decrease in circulating glucocorticoid levels have implications on cholangiocyte proliferation. Our proposed work will focus on three specific aims that have been designed to test the following working hypotheses: (1) Decreased HPA axis activity is a consequence of cholestasis and contributes to the resulting increased cholangiocyte proliferation, (2) Serum bile acids accumulate in the brain during cholestasis and subsequently suppresses the HPA axis via the specific uptake of bile acids by bile acid transporters into neurons of particular brain regions and subsequent activation of glucocorticoid receptors, and (3) Reactivation of the HPA axis by central administration of corticotropin releasing hormone effectively inhibits the cholangiocyte outgrowth seen during cholestasis via the glucocorticoid receptor- mediated inhibition of AP-1 and NFkB transcriptional activity. Dissecting the pathophysiological interactions between the brain and the liver during cholestatic liver diseases may lead to an enhanced understanding of the pathological processes and consequences of this particular type of live disease. This knowledge may play a paramount role in the development of therapeutic strategies for the treatment of cholangiopathies.

Public Health Relevance

The health relatedness of this application is that effective treatments are lacking for chronic cholestatic live diseases, such as primary biliary cirrhosis and primary sclerosing cholangitis. Cholestatic liver diseases are often associated with an impaired brain function that leads to dysregulated stress hormone control. The rationale for our research is that the successful completion of the studies can ultimately be expected to provide a greater understanding of cholestatic liver disease progression and increase the opportunities for the development of novel treatment paradigms for chronic liver diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Serrano, Jose
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Texas A&M University
Internal Medicine/Medicine
Schools of Medicine
College Station
United States
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Petrescu, Anca D; Grant, Stephanie; Frampton, Gabriel et al. (2018) Gulf war illness-related chemicals increase CD11b/c+ monocyte infiltration into the liver and aggravate hepatic cholestasis in a rodent model. Sci Rep 8:13147
DeMorrow, Sharon (2018) Role of the Hypothalamic-Pituitary-Adrenal Axis in Health and Disease. Int J Mol Sci 19:
Grant, Stephanie; McMillin, Matthew; Frampton, Gabriel et al. (2018) Direct Comparison of the Thioacetamide and Azoxymethane Models of Type A Hepatic Encephalopathy in Mice. Gene Expr 18:171-185
McMillin, Matthew; Grant, Stephanie; Frampton, Gabriel et al. (2018) FXR-Mediated Cortical Cholesterol Accumulation Contributes to the Pathogenesis of Type A Hepatic Encephalopathy. Cell Mol Gastroenterol Hepatol 6:47-63
Kennedy, Lindsey; Hargrove, Laura; Demieville, Jennifer et al. (2018) Blocking H1/H2 histamine receptors inhibits damage/fibrosis in Mdr2-/- mice and human cholangiocarcinoma tumorigenesis. Hepatology :
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
Petrescu, Anca D; Grant, Stephanie; Frampton, Gabriel et al. (2017) Glucocorticoids Cause Gender-Dependent Reversal of Hepatic Fibrosis in the MDR2-Knockout Mouse Model. Int J Mol Sci 18:
Wu, Nan; Nguyen, Quy; Wan, Ying et al. (2017) The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals. Lab Invest 97:843-853
Hargrove, Laura; Kennedy, Lindsey; Demieville, Jennifer et al. (2017) Bile duct ligation-induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell-deficient KitW-sh mice. Hepatology 65:1991-2004

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