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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK082435-03
Application #
8277426
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
2010-07-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$207,068
Indirect Cost
$42,728
Name
Texas A&M University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
McMillin, Matthew; DeMorrow, Sharon (2016) Effects of bile acids on neurological function and disease. FASEB J 30:3658-3668
McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew et al. (2016) Bile Acid Signaling Is Involved in the Neurological Decline in a Murine Model of Acute Liver Failure. Am J Pathol 186:312-23
McMillin, Matthew; Grant, Stephanie; Frampton, Gabriel et al. (2016) Fractalkine suppression during hepatic encephalopathy promotes neuroinflammation in mice. J Neuroinflammation 13:198
McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew et al. (2015) Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling. Mol Endocrinol 29:1720-30
Venter, Julie; Francis, Heather; Meng, Fanyin et al. (2015) Development and functional characterization of extrahepatic cholangiocyte lines from normal rats. Dig Liver Dis 47:964-72
McMillin, Matthew A; Frampton, Gabriel A; Seiwell, Andrew P et al. (2015) TGFβ1 exacerbates blood-brain barrier permeability in a mouse model of hepatic encephalopathy via upregulation of MMP9 and downregulation of claudin-5. Lab Invest 95:903-13
Ray, Debolina; Han, Yuyan; Franchitto, Antonio et al. (2015) Gonadotropin-releasing hormone stimulates biliary proliferation by paracrine/autocrine mechanisms. Am J Pathol 185:1061-72
McMillin, Matthew; Frampton, Gabriel; Tobin, Richard et al. (2015) TGR5 signaling reduces neuroinflammation during hepatic encephalopathy. J Neurochem 135:565-76
Han, Yuyan; Onori, Paolo; Meng, Fanyin et al. (2014) Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis. Am J Physiol Gastrointest Liver Physiol 307:G894-904
McMillin, Matthew; Frampton, Gabriel; Thompson, Michelle et al. (2014) Neuronal CCL2 is upregulated during hepatic encephalopathy and contributes to microglia activation and neurological decline. J Neuroinflammation 11:121

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