Alcoholic liver disease (ALD) continues to be a major public health problem and remains the leading cause of mortality in patients with chronic liver disease. Ethanol disrupts the pathways of energy metabolism by inhibiting AMP kinase (AMPK), and interferes with the activity of sterol response element binding protein (SREBP) and peroxisome proliferator activated receptor (PPAR), leading to alcoholic steatosis. Ethanol can induce endotoxemia. Lipopolysaccharide (LPS), a component of endotoxin, can stimulate Kupffer cells (KC), to produce cytokines. We hypothesize that LPS stimulates KC to release TNFa, which is central to the pathogenesis of alcoholic fatty liver disease through its effect on PPARa, SREBP, and AMPK. We will also study the role of other cytokines released by the macrophages (i.e., MCP-1) on these regulatory proteins. We plan to test our hypothesis by pursuing the following specific aims. 1) Determine the effect of exogenous TNFa or LPS in the presence or absence of ethanol on the function of PPARa, SREBP-1, and AMPK in McA-RH7777 hepatoma cells and isolated hepatocytes, 2) Determine the effect of LPS, in the presence or absence of ethanol, on the ability of macrophages, RAW 264.7 cells or KC, to modify the function of PPARa, SREBP-1, and AMPK in hepatoma cells and hepatocytes, 3) Determine the effects of co-culture of RAW 264.7 cells (or KC) with McA-RH7777 cells (or isolated hepatocytes) on lipid metabolism of the hepatoma cells (or isolated hepatocytes), and 4) Determine the ability of hepatoma cells or hepatocytes to modify the response of RAW cells or KC to release TNFa when stimulated by LPS, in the presence or absence of ethanol. The candidate is as Assistant Professor of Clinical Medicine. To date the candidate has trained in the laboratory of Dr. David Crabb, acquiring basic molecular biology knowledge and laboratory skills. This proposal is a logical extension of the work in this lab designed to allow the candidate to develop a basic understanding of the roles of cytokines in the pathogenesis of ALD. The candidate will develop new research skills by working with a number of experts in Kupffer cell biology, lipid metabolism, and TNF signaling, as well as through course work in molecular biology and immunology. By acquiring the knowledge and skills outlined in this proposal, the candidate hopes to fulfill his career goal of becoming a well-trained and funded physician scientist.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AA016570-05
Application #
8270609
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Radaeva, Svetlana
Project Start
2008-06-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$134,131
Indirect Cost
$7,000
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Patel, Suhag; Jinjuvadia, Raxitkumar; Patel, Ravi et al. (2016) Insulin Resistance is Associated With Significant Liver Fibrosis in Chronic Hepatitis C Patients: A Systemic Review and Meta-Analysis. J Clin Gastroenterol 50:80-4
Shen, Huafeng; Liangpunsakul, Suthat (2016) Histamine H2-Receptor Antagonist Use Is Associated With Lower Prevalence of Nonalcoholic Fatty Liver Disease: A Population-based Study From the National Health and Nutrition Examination Survey, 2001-2006. J Clin Gastroenterol 50:596-601
Jinjuvadia, Raxitkumar; Antaki, Fadi; Lohia, Prateek et al. (2016) The Association Between Nonalcoholic Fatty Liver Disease and Metabolic Abnormalities in The United States Population. J Clin Gastroenterol :
Tao, Rongya; Xiong, Xiwen; Liangpunsakul, Suthat et al. (2015) Sestrin 3 protein enhances hepatic insulin sensitivity by direct activation of the mTORC2-Akt signaling. Diabetes 64:1211-23
Liangpunsakul, Suthat (2015) Carbohydrate-responsive element-binding protein, Sirtuin 1, and ethanol metabolism: A complicated network in alcohol-induced hepatic steatosis. Hepatology 62:994-6
Gough, Gina; Heathers, Laura; Puckett, Deonna et al. (2015) The Utility of Commonly Used Laboratory Tests to Screen for Excessive Alcohol Use in Clinical Practice. Alcohol Clin Exp Res 39:1493-500
Lai, Xianyin; Liangpunsakul, Suthat; Li, Kaigang et al. (2015) Proteomic profiling of human sera for discovery of potential biomarkers to monitor abstinence from alcohol abuse. Electrophoresis 36:556-63
Zhou, Peng; Werner, John H; Lee, Donghoon et al. (2015) Dissociation between diurnal cycles in locomotor activity, feeding behavior and hepatic PERIOD2 expression in chronic alcohol-fed mice. Alcohol 49:399-408
Jinjuvadia, Raxitkumar; Liangpunsakul, Suthat; Translational Research and Evolving Alcoholic Hepatitis Treatment Consortium (2015) Trends in Alcoholic Hepatitis-related Hospitalizations, Financial Burden, and Mortality in the United States. J Clin Gastroenterol 49:506-11
Liangpunsakul, Suthat; Lai, Xianyin; Ross, Ruth A et al. (2015) Novel serum biomarkers for detection of excessive alcohol use. Alcohol Clin Exp Res 39:556-65

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