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
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
Jinjuvadia, Raxitkumar; Liangpunsakul, Suthat; Antaki, Fadi (2014) Past exposure to hepatitis B: a risk factor for increase in mortality? J Clin Gastroenterol 48:267-71
Jinjuvadia, Raxitkumar; Liangpunsakul, Suthat (2014) Association between metabolic syndrome and its individual components with viral hepatitis B. Am J Med Sci 347:23-7
Jinjuvadia, Raxitkumar; Patel, Suhag; Liangpunsakul, Suthat (2014) The association between metabolic syndrome and hepatocellular carcinoma: systemic review and meta-analysis. J Clin Gastroenterol 48:172-7
Chayanupatkul, Maneerat; Liangpunsakul, Suthat (2014) Alcoholic hepatitis: a comprehensive review of pathogenesis and treatment. World J Gastroenterol 20:6279-86
Kang, Xinqin; Petyaykina, Kateryna; Tao, Rongya et al. (2014) The inhibitory effect of ethanol on Sestrin3 in the pathogenesis of ethanol-induced liver injury. Am J Physiol Gastrointest Liver Physiol 307:G58-65
Sueblinvong, Viranuj; Liangpunsakul, Suthat (2014) Relationship between serum leptin and chronic obstructive pulmonary disease in US adults: results from the third National Health and Nutrition Examination Survey. J Investig Med 62:934-7
Chayanupatkul, Maneerat; Liangpunsakul, Suthat (2014) Cirrhotic cardiomyopathy: review of pathophysiology and treatment. Hepatol Int 8:308-15
Zhou, Peng; Ross, Ruth A; Pywell, Cameron M et al. (2014) Disturbances in the murine hepatic circadian clock in alcohol-induced hepatic steatosis. Sci Rep 4:3725
Liangpunsakul, Suthat; Bennett, Rachel; Westerhold, Chi et al. (2014) Increasing serum pre-adipocyte factor-1 (Pref-1) correlates with decreased body fat, increased free fatty acids, and level of recent alcohol consumption in excessive alcohol drinkers. Alcohol 48:795-800

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