The overall objective of this research plan has been to define the mechanisms responsible for repair and regeneration of alcohol-injured livers. After demonstrating that chronic consumption of alcohol inhibited proliferation of mature hepatocytes, we began to investigate whether liver progenitors were responsible for regenerating livers with alcohol-induced damage. During the last funding period we discovered that the Hedgehog (Hh) pathway regulates the fate of adult liver progenitors, and showed that this pathway is dramatically induced during alcoholic liver disease (ALD). Although Hh signaling was known to play critical roles in embryonic tissue construction, certain types of adult tissue remodeling, and tumor metastasis, it had not been implicated in adult liver repair until our work. Further efforts focused on delineating the pathobiological relevance of Hh pathway activation during ALD. We proved that Hh pathway activation causes liver epithelial progenitors to undergo epithelial-to-mesenchymal transition (EMT) and demonstrated that mice with an overly-active Hh pathway develop excessive liver fibrosis when their livers are injured. Our most recent preliminary data identify a novel mechanism for Hh pathway inhibition by demonstrating that Tweak/Fn14 signaling (which is known to promote expansion of epithelial-type liver progenitors) antagonizes the EMT-promoting actions of the Hh pathway and permits mesenchymal-to-epithelial transition (MET) in progenitors. Therefore, this competing renewal application will evaluate the HYPOTHESIS that the Hh pathway and Tweak/Fn14 differentially regulate the fate of liver progenitors, and hence the outcomes of ALD.
Our Specific Aims are to 1) determine if dysregulated Hh signaling increases EMT and inhibits MET to promote fibrogeneic repair of ALD, 2) determine if Tweak/Fn14 inhibit EMT and promote non-fibrogenic repair of ALD by inhibiting Hh activity, and 3) determine if treatments that improve ALD decrease EMT and enhance MET because they inhibit Hh pathway activity and/or increase Tweak/Fn14 signaling. The results will clarify the relative significance of EMT/MET, and some of the mechanisms that regulate these processes, in controlling the divergent outcomes of ALD. This, in turn, might identify novel genetic susceptibility factors for alcohol-related cirrhosis, new biomarkers for ALD progression, and novel therapeutic targets for this common liver disease.

Public Health Relevance

The results will clarify the relative significance of EMT/MET, and some of the mechanisms that regulate these processes, in controlling the divergent outcomes of ALD. This, in turn, might identify novel genetic susceptibility factors for alcohol-related cirrhosis, new biomarkers for ALD progression, and novel therapeutic targets for this common liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AA010154-17
Application #
8306351
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Gao, Peter
Project Start
1994-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
17
Fiscal Year
2012
Total Cost
$365,257
Indirect Cost
$131,118
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Michelotti, Gregory A; Tucker, Anikia; Swiderska-Syn, Marzena et al. (2016) Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches. Gut 65:683-92
Machado, Mariana Verdelho; Kruger, Leandi; Jewell, Mark L et al. (2016) Vitamin B5 and N-Acetylcysteine in Nonalcoholic Steatohepatitis: A Preclinical Study in a Dietary Mouse Model. Dig Dis Sci 61:137-48
Machado, M V; Michelotti, G A; Jewell, M L et al. (2016) Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease. Cell Death Dis 7:e2096
Swiderska-Syn, Marzena; Xie, Guanhua; Michelotti, Gregory A et al. (2016) Hedgehog regulates yes-associated protein 1 in regenerating mouse liver. Hepatology 64:232-44
Verdelho Machado, Mariana; Diehl, Anna Mae (2016) Role of Hedgehog Signaling Pathway in NASH. Int J Mol Sci 17:
Markowitz, Geoffrey J; Michelotti, Gregory A; Diehl, Anna Mae et al. (2015) Inflammatory models drastically alter tumor growth and the immune microenvironment in hepatocellular carcinoma. Sci Bull (Beijing) 60:762-772
Coombes, J D; Swiderska-Syn, M; Dollé, L et al. (2015) Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice. Gut 64:1120-31
Guy, Cynthia D; Suzuki, Ayako; Abdelmalek, Manal F et al. (2015) Treatment response in the PIVENS trial is associated with decreased Hedgehog pathway activity. Hepatology 61:98-107
Uschner, Frank E; Ranabhat, Ganesh; Choi, Steve S et al. (2015) Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension. Sci Rep 5:14573
Diehl, Anna Mae (2015) Prometheus and progenitors. Hepatology 61:1427-9

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