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 undergo ductopenia. 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 (NPY) and corticoptropin releasing hormone (CRH) are altered in models of biliary proliferation. Furthermore, we have recently demonstrated that the hypothalamic-pituitary-adrenal axis (HPA) is dampened during extrahepatic biliary obstruction resulting in suppressed glucocorticoid levels. 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 over cholangiocyte proliferation. The objective of this proposal is to investigate mechanisms by which extrahepatic biliary obstruction regulates the peripheral and central expression and activity of orexigenic peptides, and the subsequent effects on cholangiocyte proliferation. Based upon strong preliminary data, we propose the novel central hypothesis that early release of bile acids into the serum as a result of cholestasis results in the suppression of ghrelin expression from the stomach and increased production of leptin from adipose tissue. This imbalance results in the subsequent suppression of NPY and increase in ?melanocyte stimulating hormone (?MSH) expression in the hypothalamus, both of which are exacerbated by hypothalamic bile acid signaling. These peripheral and central changes in neuropeptide expression co-ordinately regulate cholangiocyte proliferation and biliary fibrosis. Our proposed work will focus on two specific aims that have been designed to test the following working hypotheses: 1) The imbalance between ghrelin and leptin during cholestasis is a result of aberrant bile acid signaling in the periphery and contributes to the resulting liver pathology; and 2) Hypothalamic NPY and ?MSH are altered as a consequence of co-ordinate bile acid signaling in the hypothalamus and alterations in the peripheral ghrelin/leptin balance. 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 liver 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 grant proposal arises from the lack of effective treatments for chronic cholestatic liver diseases, such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Chronic cholestatic liver diseases (cholangiopathies) cause proliferation/damage of bile ducts inside the liver. The rationale for this research proposal is that we expect the successful completion of the studies to provide greater understanding of the progressive mechanisms of cholestatic liver diseases, and increase opportunities for the development of novel treatment paradigms for the management of 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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Burgess-Beusse, Bonnie L
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Texas A&M University
Internal Medicine/Medicine
Schools of Medicine
College Station
United States
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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. (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; 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:

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