The pathogenesis of alcohol-induced liver injury is very complex and undoubtedly involves the interplay of multiple mechanisms and pathways, dysfunction of cellular organelles, and interactions of intrinsic and environmental factors. The chronic feeding of alcohol leads to even more complexity as these processes of intracellular and intercellular injury and repair progress. We have focused our research on role of mitochondrial and ER stress responses in the evolution of alcohol-induced liver disease. We have obtained considerable data indicating that both mitochondria and ER are damaged by chronic alcohol consumption and that prolonged mitochondrial and ER stress responses contribute to liver injury including hepatic necroinflammation and cell death and severe fatty liver leading to fibrosis and cirrhosis. How alcohol regulates genetically and epigenetically the stress response genes of the two organelles is not known. To define the mechanisms by which alcohol consumption derails the mitochondrial and ER protective responses into injury promoting processes, we hypothesize that alcohol causes aberrant recruitment of transcription factors and epigenetic changes on the mitochondrial and ER stress response gene promoters which lead to liver injury. We propose to test the possibilities.
The specific aims are: 1. Using quantitative PCR (qPCR) and ChIP assays, we will study the recruitment of promoter specific transcription factors (XBP-1, CHOP, ATF6, ATF4, CREB, TORC3, PGC-1a), general transcription factors (Pol II, NF-Y, NFR, Sp1, TBP and p300) and epigenetic marks (methylation of H3-K4 and H3-K79 and acetylation of H3 and H4) in promoters of mitochondrial and ER stress response genes (Grp78, Grp94, PDI, Calreticulin, HSP10, and HSP 60) by treating primary mouse hepatocytes with respective mitochondria and ER stress inducing agents;2. We will perform in vivo study and measure the same parameters as described in Aim 1 with qPCR and ChIP assays by feeding mice alcohol compared to pair-fed control;3. We will utilize Lox-Cre system as well as Dox-Tet advanced system to create and characterize liver specific Grp78 gene knockout mice;4. We will determine effects of Grp78 deletion on the transcription factor recruitment and epigenetic changes on the two organelle gene promoters in the liver of mice fed alcohol, couple ER stress to mitochondrial dysfunction, and assess specific contribution of ER stress to alcohol-induced liver injury. Our overall goal is to reveal transcriptional and epigenetic abnormal regulation of the two organelle stress responses by alcohol in relation to the pathogenesis of alcoholic liver disease. We anticipate that this work will lead to new approaches to prevent or treat alcoholic liver disease and will be widely applicable in other types of liver disease.

Public Health Relevance

Chronic excessive alcohol use leads to severe fatty liver and injury and is a leading cause of liver-related death and transplantation in the United States. We have identified links between liver disease and prolonged mitochondrial and ER stress responses caused by alcohol in animal models. This research is to understand how alcohol promotes injury processes in the two organelles and how organelle damages contribute to liver disease which will open new avenues for preventing and treating liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA018846-04
Application #
8316434
Study Section
Special Emphasis Panel (ZAA1-JJ (06))
Program Officer
Orosz, Andras
Project Start
2009-09-15
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$366,123
Indirect Cost
$140,121
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Ji, Cheng (2015) Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage. Biomolecules 5:1099-121
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Ji, Cheng (2014) New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases. Int J Hepatol 2014:513787
Lau, Mo Yin; Han, Hui; Hu, Jay et al. (2013) Association of cyclin D and estrogen receptor α36 with hepatocellular adenomas of female mice under chronic endoplasmic reticulum stress. J Gastroenterol Hepatol 28:576-83
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Lu, Ling; Feng, Min; Gu, Jia et al. (2013) Restoration of intrahepatic regulatory T cells through MMP-9/13-dependent activation of TGF-β is critical for immune homeostasis following acute liver injury. J Mol Cell Biol 5:369-79
Han, Hui; Hu, Jay; Lau, Mo Y et al. (2013) Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors. Front Genet 4:224
Kao, Eddy; Shinohara, Masao; Feng, Min et al. (2012) Human immunodeficiency virus protease inhibitors modulate Ca2+ homeostasis and potentiate alcoholic stress and injury in mice and primary mouse and human hepatocytes. Hepatology 56:594-604

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