Alcohol abuse is a leading cause of morbidity and mortality worldwide and recent data indicate that alcoholic liver disease affects over 10 million Americans. Epidemiological studies suggest that alcohol consumption also modulates the risk for the development of type 2 diabetes, the most common metabolic disease among older North Americans, with light alcohol consumption decreasing risk and chronic heavy alcohol consumption increasing risk in a J-shaped curve. Chronic, heavy ethanol exposure results in the development of glucose intolerance and hepatic insulin resistance. While the role of adipose tissue in the regulation of energy stores has long been appreciated, there is a growing understanding for the critical role of adipose tissue in regulating metabolic homeostasis, including the ability to modulate insulin sensitivity in skeletal muscle and liver, as well as contribute to the regulation of inflammatory responses. The long-term goals of this research project are to investigate the mechanisms by which ethanol disrupts the metabolic activity of adipose tissue and determine the impact of these chronic ethanol-induced changes in adipose tissue on the pathophysiological effects of chronic ethanol in liver. In the past granting period, we have shown that chronic ethanol feeding increases the infiltration of macrophages into adipose tissue associated with increased the expression of inflammatory cytokines and chemokines, as well as decreases in adiponectin secretion. Here we hypothesize that changes in the metabolic and regulatory activity of adipose tissue in response to chronic ethanol consumption are important contributors to the development of ethanol-induced liver injury. In this proposed renewal, we will investigate the mechanisms by which chronic ethanol exposure increases inflammatory cytokine expression and decreases adiponectin expression and secretion by adipose tissue. Utilizing mouse and rat models of chronic ethanol exposure, the specific aims of this proposal are to test the following hypotheses: 1) Ethanol-induced oxidant stress in adipose tissue leads to macrophage recruitment and an increased inflammatory milieu in adipose tissue. 2) Decreased circulating adiponectin after chronic ethanol exposure is due to ethanol-induced decreases in adiponectin expression and secretion and 3) Ethanol-induced disruption of adipose tissue metabolism, leading to decreased adiponectin secretion by adipose tissue, contributes to ethanol-induced liver injury. Understanding the mechanisms by which chronic ethanol disrupts the metabolic and regulatory activity of adipose tissue, and the impact of these changes on hepatic function, will likely lead to the development of novel therapeutic strategies to prevent and/or reverse alcoholic liver disease.

Public Health Relevance

Alcohol abuse is a leading cause of morbidity and mortality worldwide and recent data indicate that alcoholic liver disease affects over 10 million Americans. The long-term goals of this research project are to investigate the mechanisms by which ethanol disrupts the metabolic activity of adipose tissue and determine the impact of these chronic ethanol-induced changes in adipose tissue in the development of alcoholic liver disease. Understanding the mechanisms by which chronic ethanol disrupts the metabolic and regulatory activity of adipose tissue, and the impact of these changes on hepatic function, will likely lead to the development of novel therapeutic strategies to prevent and/or reverse alcoholic 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 #
5R37AA011876-15
Application #
8299984
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Radaeva, Svetlana
Project Start
1998-04-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
15
Fiscal Year
2012
Total Cost
$396,436
Indirect Cost
$143,353
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Roychowdhury, Sanjoy; McCullough, Rebecca L; Sanz-Garcia, Carlos et al. (2016) Receptor interacting protein 3 protects mice from high-fat diet-induced liver injury. Hepatology 64:1518-1533
Smathers, Rebecca L; Chiang, Dian J; McMullen, Megan R et al. (2016) Soluble IgM links apoptosis to complement activation in early alcoholic liver disease in mice. Mol Immunol 72:9-18
McCullough, Rebecca L; McMullen, Megan R; Das, Dola et al. (2016) Differential contribution of complement receptor C5aR in myeloid and non-myeloid cells in chronic ethanol-induced liver injury in mice. Mol Immunol 75:122-32
Barnes, Mark A; McMullen, Megan R; Roychowdhury, Sanjoy et al. (2015) Macrophage migration inhibitory factor is required for recruitment of scar-associated macrophages during liver fibrosis. J Leukoc Biol 97:161-9
Cresci, Gail A; Allende, Daniela; McMullen, Megan R et al. (2015) Alternative complement pathway component Factor D contributes to efficient clearance of tissue debris following acute CClâ‚„-induced injury. Mol Immunol 64:9-17
Park, Pil-Hoon; Sanz-Garcia, Carlos; Nagy, Laura E (2015) Adiponectin as an anti-fibrotic and anti-inflammatory adipokine in the liver. Curr Pathobiol Rep 3:243-252
Latchoumycandane, Calivarathan; Nagy, Laura E; McIntyre, Thomas M (2015) Myeloperoxidase formation of PAF receptor ligands induces PAF receptor-dependent kidney injury during ethanol consumption. Free Radic Biol Med 86:179-90
Barnes, Mark A; Roychowdhury, Sanjoy; Nagy, Laura E (2014) Innate immunity and cell death in alcoholic liver disease: role of cytochrome P4502E1. Redox Biol 2:929-35
Latchoumycandane, Calivarathan; Nagy, Laura E; McIntyre, Thomas M (2014) Chronic ethanol ingestion induces oxidative kidney injury through taurine-inhibitable inflammation. Free Radic Biol Med 69:403-16
Dixon, Laura J; Barnes, Mark; Tang, Hui et al. (2013) Kupffer cells in the liver. Compr Physiol 3:785-97

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