Cholangiocytes are the target cells in cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). During the course of these diseases, mitotically dormant cholangiocytes are stimulated to proliferate and then are damaged. Associated with these cholangiopathies is a dysregulation of various neuroendocrine factors derived from the hypothalamus and the acquisition of a neuroendocrine phenotype in cholangiocytes. Taken together, these events contribute to the autocrine and paracrine pathways that modulate the proliferative response of cholangiocytes as well as liver damage and fibrosis in cholestatic liver injury. We have previously shown that circulating neuropeptide Y, and corticoptropin releasing hormone (CRH) are altered in models of biliary proliferation. Furthermore, we have recently demonstrated that the hypothalamic-pituitary-adrenal axis is dampened resulting in suppressed glucocorticoid levels during extrahepatic biliary obstruction and that reactivation of the HPA axis by hypothalamic administration of CRH suppresses the proliferative capacity of cholangiocytes after bile duct ligation (BDL), suggesting a broader concept of hypothalamic control of cholangiocyte proliferation. The objective of this proposal is to investigate mechanisms by which cholestasis regulates the expression of the hypothalamic peptide galanin and the subsequent effects of this altered response 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 increased hypothalamic and circulating galanin levels and that the central and peripheral effects of galanin co-ordinately regulate cholangiocyte proliferation. Our proposed work will focus on three specific aims that have been designed to test the following working hypotheses: (1) The expression of the hypothalamic peptide galanin is upregulated during cholestatic liver diseases and activates the growth hormone releasing hormone (GHRH) /growth hormone (GH) axis to induce cholangiocyte proliferation, (2) Circulating levels of galanin are increased during experimental cholestasis and can act on cholangiocytes directly to induce proliferation, and (3) The alteration of the galanin expression in the hypothalamus is a direct result of the actions of bile acids in th hypothalamus. 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 research program proposed herein is significantly relevant to the VA mission and its successful completion will likely benefit Veteran patients. The risk of liver diseases due to alcohol and toxin abuse in US Veterans is increasingly high and is one of the most common reasons for hospitalization, morbidity and mortality in US Veterans. Scientific interest in cholangiocytes (cells lining the biliary tract) is due to the fact that these cells are the target ells in cholangiopathies or diseases like primary biliary cirrhosis. Management of cholangiopathies (characterized by cholangiocyte proliferation or damage) represents one of the major challenges for the VA. These diseases are often associated with an impaired brain function that leads to dysregulated hypothalamic neuropeptide 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.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX002638-02
Application #
8967104
Study Section
Gastroenterology (GAST)
Project Start
2014-10-01
Project End
2018-09-30
Budget Start
2015-10-01
Budget End
2016-09-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Olin Teague Veterans Center
Department
Type
DUNS #
029847394
City
Temple
State
TX
Country
United States
Zip Code
76504
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
McMillin, Matthew; Frampton, Gabriel; Grant, Stephanie et al. (2017) The Neuropeptide Galanin Is Up-Regulated during Cholestasis and Contributes to Cholangiocyte Proliferation. Am J Pathol 187:819-830
McMillin, Matthew; DeMorrow, Sharon; Glaser, Shannon et al. (2017) Melatonin inhibits hypothalamic gonadotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats. Am J Physiol Gastrointest Liver Physiol 313:G410-G418
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

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