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 insulin resistance. Since insulin resistance is commonly associated with the progression of liver disease in individuals with metabolic syndrome, as well as the development of type 2 diabetes, we hypothesize that ethanol-induced insulin resistance also contributes to the progression of alcoholic liver disease. In the past granting period, we have made significant progress in understanding the molecular and cellular mechanisms by which chronic, heavy ethanol feeding results in the development of insulin resistance, both in relation to glucose and lipid homeostasis. We have identified adipose tissue as a specific target of ethanol action. 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, contribute to the regulation of inflammatory responses, as well as regulating appetitive behaviors. Given these essential roles for adipose tissue, the long-term goals of this research project are to investigate the mechanisms by which ethanol disrupts the metabolic and regulatory activity of adipose tissue and.determine the impact of these chronic ethanol-induced changes in adipose tissue in mediating the pathophysiological effects of chronic ethanol. During the extension of this research plan, we propose to investigate the hypothesis that changes in the metabolic and regulatory activity of adipose tissue in response to chronic ethanol consumption are important contributors to spreading of tissue injury between organs, particularly to the liver and kidney. We will investigate the following specific aims:
Specific Aim 1 : Determine the molecular and cellular mechanisms for activation of complement in adipose tissue after chronic ethanol exposure;
Specific Aim 2 : Determine if blockade of the Clq pathway and complement activation can prevent or reverse adipose tissue inflammation and insulin resistance after chronic ethanol;
Specific Aim 3 : Understand the broader impact on the ethanol on the adipocyte secretome and the influence of the adipose secretome in the spread of tissue injury after chronic ethanol feeding. 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.

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 #
4R37AA011876-17
Application #
8602009
Study Section
Special Emphasis Panel (NSS)
Program Officer
Gao, Peter
Project Start
1998-04-01
Project End
2019-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
17
Fiscal Year
2014
Total Cost
$415,093
Indirect Cost
$151,887
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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
Barnes, Mark A; McMullen, Megan R; Roychowdhury, Sanjoy et al. (2013) Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis. Hepatology 57:1980-91
Hillian, Antoinette D; McMullen, Megan R; Sebastian, Becky M et al. (2013) Mice lacking C1q are protected from high fat diet-induced hepatic insulin resistance and impaired glucose homeostasis. J Biol Chem 288:22565-75
Dixon, Laura J; Flask, Chris A; Papouchado, Bettina G et al. (2013) Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis. PLoS One 8:e56100
Dixon, Laura J; Barnes, Mark; Tang, Hui et al. (2013) Kupffer cells in the liver. Compr Physiol 3:785-97
Li, Qingling; Sadhukhan, Sushabhan; Berthiaume, Jessica M et al. (2013) 4-Hydroxy-2(E)-nonenal (HNE) catabolism and formation of HNE adducts are modulated by ýý oxidation of fatty acids in the isolated rat heart. Free Radic Biol Med 58:35-44
Tang, Hui; Sebastian, Becky M; Axhemi, Armend et al. (2012) Ethanol-induced oxidative stress via the CYP2E1 pathway disrupts adiponectin secretion from adipocytes. Alcohol Clin Exp Res 36:214-22
Sebastian, Becky M; Roychowdhury, Sanjoy; Tang, Hui et al. (2011) Identification of a cytochrome P4502E1/Bid/C1q-dependent axis mediating inflammation in adipose tissue after chronic ethanol feeding to mice. J Biol Chem 286:35989-97
Mandal, Palash; Pratt, Brian T; Barnes, Mark et al. (2011) Molecular mechanism for adiponectin-dependent M2 macrophage polarization: link between the metabolic and innate immune activity of full-length adiponectin. J Biol Chem 286:13460-9

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