This project is designed to investigate the effects of ethanol on the activities of peroxisome proliferator activated receptor (PPARs) and sterol regulatory element (SRE)-binding protein (SREBPs). We have determined that ethanol treatment of hepatoma cells or hepatocytes decreases the ability of PPARalpha to activate a PPAR responsive reporter plasmid. This effect of ethanol depends on ethanol metabolism and is mediated by acetaldehyde. Further, in nuclear extracts from ethanol-treated cells, we have noted decreased binding of the PPARalpha/RXRalpha heterodimer to an oligonucleotide containing the PPAR response element. We have also found that ethanol treatment increases SREBP-regulated transcription of a SRE reporter in a dose-dependent manner in two hepatoma cell lines but not in CV-1 cells, suggesting that ethanol metabolism is also required for this effect. This effect is mediated via the SREBP proteolytic maturation cascade and is blocked by increasing concentration of sterols. We hypothesize that ethanol causes the development and maintenance of fatty liver by effects on these transcription factors, in addition to its well known effects on redox state and oxidative stress. This will be tested in both animals and cell culture models. We will examine the effect of alcohol feeding on levels of PPARs, their DNA-binding activity, levels of PPAR-regulated mRNAs, and responsiveness to WY14643. We will examine the effects of alcohol feeding on levels of SREBP-regulated mRNAs, and responsiveness of the system to cholesterol and metformin. The activities of these transcription factors and the genes they regulate will be correlated with hepatic histology, lipid content, and measures of total body lipid metabolism. Mechanisms for these activities of alcohol will be tested in hepatoma cells to better understand the molecular basis for the effects. Since these pathways can be manipulated by pharmacological agents, this hypothesis suggests possible new therapies for alcoholic fatty liver and possibly steatohepatitis.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Purohit, Vishnu
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Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
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You, Min (2018) Obesity and Binge Drinking: Two Hits Driving Liver Fibrosis Progression? Cell Mol Gastroenterol Hepatol 5:424-425
You, Min; Zhou, Zhou; Daniels, Michael et al. (2018) Endocrine Adiponectin-FGF15/19 Axis in Ethanol-Induced Inflammation and Alcoholic Liver Injury. Gene Expr 18:103-113
You, Min; Jogasuria, Alvin; Lee, Kwangwon et al. (2017) Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1. Curr Mol Pharmacol 10:226-236
Xu, Jiesi; Xu, Yang; Li, Yuanyuan et al. (2016) Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4? and Protects Against Alcohol- and MCD diet-induced Liver Injury. Sci Rep 6:24277
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
Odena, Gemma; Chen, Jiegen; Lozano, Juan Jose et al. (2016) LPS-TLR4 Pathway Mediates Ductular Cell Expansion in Alcoholic Hepatitis. Sci Rep 6:35610
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
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
You, Min; Jogasuria, Alvin; Taylor, Charles et al. (2015) Sirtuin 1 signaling and alcoholic fatty liver disease. Hepatobiliary Surg Nutr 4:88-100
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

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