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.
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.
|Hu, Jay; Han, Hui; Lau, Mo Yin et al. (2015) Effects of combined alcohol and anti-HIV drugs on cellular stress responses in primary hepatocytes and hepatic stellate and kupffer cells. Alcohol Clin Exp Res 39:11-20|
|Ji, Cheng (2015) Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage. Biomolecules 5:1099-121|
|Zhang, Huiying; Lv, Minli; Zhao, Zhongfu et al. (2014) Glucose-regulated protein 78 may play a crucial role in promoting the pulmonary microvascular remodeling in a rat model of hepatopulmonary syndrome. Gene 545:156-62|
|Zhang, Huiying; Lv, Minli; Jia, Jiantao et al. (2014) Expression of the 78 kD glucose-regulated protein is induced by endoplasmic reticulum stress in the development of hepatopulmonary syndrome. Gene 537:115-9|
|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 ?36 with hepatocellular adenomas of female mice under chronic endoplasmic reticulum stress. J Gastroenterol Hepatol 28:576-83|
|Liu, Yang; Du, Juanjuan; Yan, Ming et al. (2013) Biomimetic enzyme nanocomplexes and their use as antidotes and preventive measures for alcohol intoxication. Nat Nanotechnol 8:187-92|
|Lu, Ling; Feng, Min; Gu, Jia et al. (2013) Restoration of intrahepatic regulatory T cells through MMP-9/13-dependent activation of TGF-? 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|
Showing the most recent 10 out of 19 publications