Alcoholic liver disease (ALD) is a major cause of liver disease and liver related morbidity/mortality in the United States. One major difficulty in devising specific therapies for ALD has been our limited understanding of the mechanism(s) for the development and progression of this liver injury. Cytokines are low molecular weight mediators of cellular communication that are produced and released by numerous cell types such as monocytes, macrophages, and of particular relevance to liver disease, Kupffer cells. Pro-inflammatory cytokines, such as tumor necrosis factor a (TNF), and chemokines, such as interleukin-8, have been postulated to play a role in modulating many of the systemic manifestations of ALD and certain aspects of the liver injury in ALD. Many factors stimulate cytokine production, including endotoxin (lipopolysaccharide or LPS) and reactive oxygen intermediates (ROIs), both of which are of direct relevance to this proposal. Endotoxin stimulates cytokine production via interaction with LPS binding protein (LBP); membrane bound CD 14, and ultimately the recently described LPS receptor, Toll-like receptor TLR4. TLR4 then causes activation of the redox sensitive transcription factor, NFkB, with subsequent production of cytokines such as TNF. NFKB also has been identified as a survival factor against TNF induced apoptosis in multiple cell types. Thus, NFKB not only serves as a transcription factor for several inflammatory cytokines such as TNF and IL-8, but also for several potentially protective factors such as inhibitors of apoptosis (lAPs). Inhibition of NFkB can initiate fulminant liver injury and hepatocyte apoptosis, at least in part, by allowing unregulated signaling via the TNF """"""""death domain."""""""" We postulate that in ALD there is: 1) increased NFkB activation and TNF production in the major cytokine producing cell in the liver (Kupffer cell); and 2) decreased NFkB activation and decreased """"""""protective signaling"""""""" in conjunction with increased TNF death signaling in the target cell (hepatocyte). In this proposal, we will use in vitro systems, in vivo animal models of ALD and ultimately will perform translational human studies to further define mechanisms of liver injury in ALD and potential pathways for intervention.
The specific aims of this proposal are to: 1) Evaluate mechanisms for increased NFkB activation and TNF production by monocyte/Kupffer cells in ALD (priming), 2) Evaluate mechanisms of increased susceptibility to TNF/cytokine hepatotoxicity in ALD (sensitization).

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 #
5R37AA010762-08
Application #
6618142
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Purohit, Vishnu
Project Start
1996-03-01
Project End
2006-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
8
Fiscal Year
2002
Total Cost
$357,500
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40292
Song, Ming; Chen, Theresa; Prough, Russell A et al. (2016) Chronic Alcohol Consumption Causes Liver Injury in High-Fructose-Fed Male Mice Through Enhanced Hepatic Inflammatory Response. Alcohol Clin Exp Res 40:518-28
Vatsalya, Vatsalya; Pandey, Akash; Schwandt, Melanie L et al. (2016) Safety Assessment of Liver Injury with Quetiapine Fumarate XR Management in Very Heavy Drinking Alcohol-Dependent Patients. Clin Drug Investig 36:935-944
Liu, Yanlong; Zhao, Cuiqing; Xiao, Jian et al. (2016) Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury. Sci Rep 6:31026
Zhao, Cuiqing; Liu, Yanlong; Xiao, Jian et al. (2015) FGF21 mediates alcohol-induced adipose tissue lipolysis by activation of systemic release of catecholamine in mice. J Lipid Res 56:1481-91
Song, Ming; Schuschke, Dale A; Zhou, Zhanxiang et al. (2015) Kupffer cell depletion protects against the steatosis, but not the liver damage, induced by marginal-copper, high-fructose diet in male rats. Am J Physiol Gastrointest Liver Physiol 308:G934-45
Liu, Huilin; Beier, Juliane I; Arteel, Gavin E et al. (2015) Transient receptor potential vanilloid 1 gene deficiency ameliorates hepatic injury in a mouse model of chronic binge alcohol-induced alcoholic liver disease. Am J Pathol 185:43-54
Liu, Yanlong; Ma, Zhenhua; Zhao, Cuiqing et al. (2014) HIF-1? and HIF-2? are critically involved in hypoxia-induced lipid accumulation in hepatocytes through reducing PGC-1?-mediated fatty acid ?-oxidation. Toxicol Lett 226:117-23
Shi, Xue; Wei, Xiaoli; Koo, Imhoi et al. (2014) Metabolomic analysis of the effects of chronic arsenic exposure in a mouse model of diet-induced Fatty liver disease. J Proteome Res 13:547-554
Ghare, Smita S; Joshi-Barve, Swati; Moghe, Akshata et al. (2014) Coordinated histone H3 methylation and acetylation regulate physiologic and pathologic fas ligand gene expression in human CD4+ T cells. J Immunol 193:412-21
Watson, Walter H; Burke, Tom J; Doll, Mark A et al. (2014) S-adenosylhomocysteine inhibits NF-?B-mediated gene expression in hepatocytes and confers sensitivity to TNF cytotoxicity. Alcohol Clin Exp Res 38:889-96

Showing the most recent 10 out of 54 publications