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 #
5R37AA010154-16
Application #
8112587
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Radaeva, Svetlana
Project Start
1994-08-01
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
16
Fiscal Year
2011
Total Cost
$365,257
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Chen, Jiamei; Chen, Long; Zern, Mark A et al. (2017) The diversity and plasticity of adult hepatic progenitor cells and their niche. Liver Int 37:1260-1271
Xie, Guanhua; Swiderska-Syn, Marzena; Jewell, Mark L et al. (2017) Loss of pericyte smoothened activity in mice with genetic deficiency of leptin. BMC Cell Biol 18:20
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
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
Machado, Mariana Verdelho; Diehl, Anna Mae (2016) Pathogenesis of Nonalcoholic Steatohepatitis. Gastroenterology 150:1769-77
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
Verdelho Machado, Mariana; Diehl, Anna Mae (2016) Role of Hedgehog Signaling Pathway in NASH. Int J Mol Sci 17:
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
Karaca, Gamze; Xie, Guanhua; Moylan, Cynthia et al. (2015) Role of Fn14 in acute alcoholic steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol 308:G325-34
Diehl, Anna Mae (2015) Prometheus and progenitors. Hepatology 61:1427-9

Showing the most recent 10 out of 30 publications