Alcoholic steatohepatitis is characterized by hepatic steatosis, inflammatory infiltrate, and progression to liver fibrosis. It is one of the most prevalnt forms of chronic liver disease which may progress to fibrosis, cirrhosis, hepatocellular cancer. The underlying mechanisms by which ethanol consumption leads to steatosis/steatohepatitis are multiple, complex and incompletely understood. This grant is currently in its 10th year and has supported 29 original papers and 6 reviews. During the 10 year grant period, we have discovered that chronic ethanol consumption causes the development and maintenance of fatty liver in mice by affecting several important liver transcriptional regulators involved in controls pathways of lipid metabolism;namely, sterol regulatory element binding protein 1 (SREBP-1), PPAR-gamma co-activator-alpha (PGC-1-alpha) and AMP-activated kinase (AMPK). More importantly, sirtuin 1 (SIRT1), an NAD+-dependent class III protein deacetylase, has been identified as a vital bridging molecule that links ethanol metabolism with downstream effects (including activation of aforementioned transcriptional regulators and the expression of genes that ultimately promote lipid accumulation and inflammation). In the past funding cycle, our group has further investigated the underlying mechanisms of ethanol-mediated hepatic SIRT1 inhibition by identifying a new hepatic target of ethanol action, microRNA-217 (miR-217). We found that ethanol drastically and specifically up-regulates hepatic miR-217, and inhibits SIRT1, and ultimately causes excessive accumulation of lipid and inflammation. Therefore, this current proposal examines a novel and exciting hypothesis that hepatic miR-217 plays a vital role in the development of alcoholic steatohepatitis. The three Specific Aims of the proposal are to: (1) Investigate the role of miR-217 in the development of alcoholic steatohepatitis in mice. (2) Investigate the underlying mechanisms by which ethanol up-regulates miR-217 and causes steatosis in cultured hepatocytes and in mouse livers. (3) Investigate the underlying mechanisms by which ethanol up- regulates miR-217 and causes inflammation in cultured Kupffer cells and in mouse livers. We will utilize state- of-the-art molecular, cellular, and biochemical approaches with cell culture and genetically or adenoviral modified mouse models to dissect the signaling events mediating the action of ethanol on hepatic miR-217- SIRT1 axis. The long term goal of this research project is to translate our findings from the laboratory to bedside to better understand the mechanisms underlying alcoholic steatosis/steatohepatitis, and to ultimately discover novel targets and therapeutic approaches for preventing and treating human alcoholic steatosis/steatohepatitis.

Public Health Relevance

Sirtuin 1 (SIRT1), an NAD+-dependent class III protein deacetylase, is a master regulator of the transcriptional networks that control hepatic lipid metabolism and inflammation. This renewal application will study the molecular mechanisms by which ethanol inhibits SIRT1 and impairs its hepatic signaling. This study will increase our knowledge of the pathogenesis and therapeutics for treatment of human alcoholic steatosis/ steatohepatitis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA013623-12
Application #
8628958
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Gao, Peter
Project Start
2002-04-01
Project End
2019-06-30
Budget Start
2014-09-10
Budget End
2015-06-30
Support Year
12
Fiscal Year
2014
Total Cost
$151,600
Indirect Cost
$51,600
Name
Northeast Ohio Medical University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
077779882
City
Rootstown
State
OH
Country
United States
Zip Code
44272
Hu, Xudong; Jogasuria, Alvin; Wang, Jiayou et al. (2016) MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis. J Biol Chem 291:22482-22495
Cai, Yan; Jogasuria, Alvin; Yin, Huquan et al. (2016) The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice. Am J Pathol 186:2417-28
Wang, Jiayou; Kim, Chunki; Jogasuria, Alvin et al. (2016) Myeloid Cell-Specific Lipin-1 Deficiency Stimulates Endocrine Adiponectin-FGF15 Axis and Ameliorates Ethanol-Induced Liver Injury in Mice. Sci Rep 6:34117
Xu, Jiesi; Xu, Yang; Li, Yuanyuan et al. (2016) Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4α and Protects Against Alcohol- and MCD diet-induced Liver Injury. Sci Rep 6:24277
Odena, Gemma; Chen, Jiegen; Lozano, Juan Jose et al. (2016) LPS-TLR4 Pathway Mediates Ductular Cell Expansion in Alcoholic Hepatitis. Sci Rep 6:35610
You, Min; Jogasuria, Alvin; Taylor, Charles et al. (2015) Sirtuin 1 signaling and alcoholic fatty liver disease. Hepatobiliary Surg Nutr 4:88-100
You, Min; Jogasuria, Alvin; Lee, Kwangwon et al. (2015) Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emerging Role of Lipin-1. Curr Mol Pharmacol :
Yin, Huquan; Liang, Xiaomei; Jogasuria, Alvin et al. (2015) miR-217 regulates ethanol-induced hepatic inflammation by disrupting sirtuin 1-lipin-1 signaling. Am J Pathol 185:1286-96
Yin, Huquan; Hu, Ming; Liang, Xiaomei et al. (2014) Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver. Gastroenterology 146:801-11
Everitt, Hannah; Hu, Ming; Ajmo, Joanne M et al. (2013) Ethanol administration exacerbates the abnormalities in hepatic lipid oxidation in genetically obese mice. Am J Physiol Gastrointest Liver Physiol 304:G38-47

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