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.
|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|
|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|
|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|
|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|
|Than, Tin Aung; Lou, Huan; Ji, Cheng et al. (2011) Role of cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3) in the initiation of mitochondrial biogenesis and stress response in liver cells. J Biol Chem 286:22047-54|
|Dara, Lily; Ji, Cheng; Kaplowitz, Neil (2011) The contribution of endoplasmic reticulum stress to liver diseases. Hepatology 53:1752-63|
|Loftus, Neil; Barnes, Alan; Ashton, Simon et al. (2011) Metabonomic investigation of liver profiles of nonpolar metabolites obtained from alcohol-dosed rats and mice using high mass accuracy MSn analysis. J Proteome Res 10:705-13|
|Ji, Cheng; Kaplowitz, Neil; Lau, Mo Yin et al. (2011) Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice. Hepatology 54:229-39|
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