Morbidity and mortality in ALD are caused by alcohol-induced steatohepatitis (ASH), cirrhosis, and liver cancer. The mechanisms driving pathogenesis and progression of these conditions are poorly understood. Since its inception, this research program has been evaluating the over-arching hypothesis that the bad outcomes of alcohol-induced liver injury result from deregulated repair mechanisms that result in defective regeneration of mature hepatocytes. Our studies revealed that TNF alpha and related cytokines are necessary for liver regeneration, and demonstrated that regeneration of chronically injured livers involves progenitors. We have since shown that interfering with survival signaling by the TNF-regulated transcription factor, NF-kB, stimulates dying hepatocytes to produce Hedgehog (Hh) ligands. We proved that Hh ligands regulate the fate of adult liver progenitors, and demonstrated that liver progenitors retain inherent plasticity, undergoing Hh-regulated epithelial-to-mesenchymal transitions (EMT) and mesenchymal to epithelial transitions (MET) during liver repair. We will soon report that effective liver regeneration requires balanced EMT/MET in progenitors, and have other unpublished evidence that Tweak (a TNF-related cytokine) and its receptor, Fni4, interact with Hh to control this process. These discoveries are relevant to ALD because there is a striking inverse correlation between progenitor cell accumulation and mortality in patients with ASH. We believe that this reflects that fact that liver progenitors accumulate when effective regeneration of mature hepatocytes stalls. Hence, we are now focused on identifying the mechanisms that regulate progenitor-mediated regeneration of alcohol-injured livers. Assuming funding is renewed, this R37-supported research program will continue to evaluate 3 Specific Aims;
Aim 1 : Determine if dysregulated Hedgehog (Hh) signaling increases EMT and inhibits MET to promote fibrogenic repair of alcoholic liver disease (ALD) Aim 2: Determine if Tweak/Fni4 inhibits EMT and promotes non-fibrogenic repair of ALD by inhibiting Hh activity Aim 3 : Determine if treatments that improve ALD decrease EMT and enhance MET because they inhibit activity and /or increase Tweak/Fni4 signaling

Public Health Relevance

Patients already have alcoholic liver disease (ALD) when they present for medical care. Thus, a primary goal of treatment is to expedite liver repair. Successful repair regenerates mature liver cells without causing scarring or cancer. Our research is significant because it is revealing how to optimize liver repair and thus, recovery from ALD.

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 #
4R37AA010154-19
Application #
8644979
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Gao, Peter
Project Start
1994-08-01
Project End
2019-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
19
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Type
DUNS #
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
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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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