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.
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.
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