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 We will soon report that effective liver regeneration requires balanced EMT/MET in progenitors, and have other unpublished evidence that Tweak (a TNF-related cytokine) and its receptor, Fni4, interact with Hh to control this process.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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Method to Extend Research in Time (MERIT) Award (R37)
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No Study Section (in-house review) (NSS)
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Gao, Peter
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Duke University
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Machado, Mariana Verdelho; Diehl, Anna Mae (2018) Hedgehog signalling in liver pathophysiology. J Hepatol 68:550-562
Chen, Kai-Yuan; Shen, Xiling; Diehl, Anna Mae (2018) Prometheus revisited. J Clin Invest 128:2192-2193
Castro, Rui E; Diehl, Anna Mae (2018) Towards a definite mouse model of NAFLD. J Hepatol 69:272-274
Du, Kuo; Hyun, Jeongeun; Premont, Richard T et al. (2018) Hedgehog-YAP Signaling Pathway Regulates Glutaminolysis to Control Activation of Hepatic Stellate Cells. Gastroenterology 154:1465-1479.e13
Oh, Seh-Hoon; Swiderska-Syn, Marzena; Jewell, Mark L et al. (2018) Liver regeneration requires Yap1-TGF?-dependent epithelial-mesenchymal transition in hepatocytes. J Hepatol 69:359-367
Verdelho Machado, Mariana; Diehl, Anna Mae (2018) The hedgehog pathway in nonalcoholic fatty liver disease. Crit Rev Biochem Mol Biol 53:264-278
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
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

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