We have demonstrated that the intragastric alcohol fed mouse develops hyperhomocysteinemia, ER stress and steatohepatitis. Feeding betaine prevents all of these effects of alcohol. Based upon our previous studies we have developed five specific aims which test the hypothesis that ER stress induced by homocysteine plays a key role in the pathogenesis of alcoholic liver disease:
Aim 1. Determine the effect of liver specific deletion of Grp78 on the susceptibility to liver injury from alcohol or high methionine low folate (HMLF) feeding: this work includes breeding and phenotyping conditional knockout mice, and in vitro and in vivo studies of the effect of deletion of Grp78;
Aim 2. Determine the effectiveness of molecular chaperones in inhibiting alcohol and homocysteine-induced ER stress and steatohepatitis: this work includes in vitro studies as proof of principle and in vivo studies of the protective effect.
Aim 3. Examine the contribution of JNK in ER stress-induced liver injury: these studies will assess the effects of antisense to JNK1, 2, or both in vitro in proof of principle studies and in vivo studies in the alcohol and HMLF models. The first three aims test the hypothesis that ER stress is a major determinant of the severity of alcohol liver disease in the intragastric mouse model.
Aim 4. Determine the mechanism and role of ER stress in hepatic lipid accumulation by testing the hypothesis that alcoholic fatty liver is caused by ER stress induced dysregulation of Insig-1 leading to SREBP activation.
Aim 5. Determine the role of BHMT in alcohol-induced liver injury by testing the hypothesis that the response of BHMT is a critical factor in the development of hyperhomocysteinemia and subsequent downstream activation of ER stress resulting in steatosis and injury;this work will include studies of the species differences (mouse versus rat) in the transcriptional regulation of BHMT, the role of NF-kB in repression of BHMT, the mechanism of induction of BHMT by homocysteine and betaine, and the effect of inhibiting BHMT by feeding CBHcy with alcohol in the rat model to test if the resistance to alcoholic liver disease can be overcome. This work will lead to new approaches to prevent or treat alcoholic liver disease and will expand our knowledge of the causes and effects of ER stress in the liver.
Fatty liver and injury leading to cirrhosis as a consequence of chronic excessive alcohol use is a leading cause of liver-related death and transplantation in the United States. We have identified a link between liver disease and elevated homocysteine levels caused by alcohol in animal models. Therefore, understanding how alcohol increase homocysteine levels and how increased levels of homocysteine contribute to liver damage will open new avenues for preventing and treating liver disease due to alcohol and other causes.
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|Zhang, Lili; Zhang, Huiying; Lv, Minli et al. (2015) Increased expression of 78 kD glucose-regulated protein promotes cardiomyocyte apoptosis in a rat model of liver cirrhosis. Int J Clin Exp Pathol 8:9256-63|
|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|
|Win, Sanda; Than, Tin Aung; Le, Bao Han Allison et al. (2015) Sab (Sh3bp5) dependence of JNK mediated inhibition of mitochondrial respiration in palmitic acid induced hepatocyte lipotoxicity. J Hepatol 62:1367-74|
|Than, T A; Win, S; Kaplowitz, N (2014) In vitro assays of mitochondrial function/dysfunction. Clin Pharmacol Ther 96:665-8|
|Luedde, Tom; Kaplowitz, Neil; Schwabe, Robert F (2014) Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 147:765-783.e4|
|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|
|Win, S; Than, T A; Fernandez-Checa, J C et al. (2014) JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death. Cell Death Dis 5:e989|
|Ji, Cheng (2014) New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases. Int J Hepatol 2014:513787|
|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|
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