The inhibitory effect of ethanol on Sestrin3 in the pathogenesis of ethanol-induced liver injury.
Sestrins (Sesns) are a family of stress-sensitive genes that have been suggested to regulate lipid metabolism. Chronic ethanol feeding is known to cause lipid accumulation in hepatocytes. This study was designed to investigate the role of Sesn3 in the pathogenesis of alcohol-induced hepatic steatosis. We demonstrated that ethanol inhibited the expression of Sesn3 in VL-17A cells. Overexpression of Sesn3 ameliorated triglyceride accumulation; downregulation using short hairpin RNA significantly deteriorated triglyceride accumulation in these cells. The expression of Sesn3 was also reduced in mice fed with ethanol for 4 wk. Overexpression of Sesn3 prevented hepatic steatosis, whereas knockdown of Sesn3 worsened hepatic steatosis in ethanol-fed mice. Overexpression of Sesn3 significantly reduced the expression of genes encoding for lipid synthesis through AMPK pathway. Overexpression of Sesn3 augmented the effect of ethanol on phospho-p70 S6 kinase. The levels of hepatic light chain 3, a marker for autophagy, expression were significantly decreased in ethanol-fed mice after Sesn3 gene was knocked down. Our findings suggest that inhibitory effect of ethanol on Sesn3 may play an important role in the development of ethanol-induced fatty liver.
Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
Xinqin
X
Kang
Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
Kateryna
K
Petyaykina
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana; and.
Rongya
R
Tao
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana; and.
Xiwen
X
Xiong
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana; and.
X Charlie
XC
Dong
Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Roudebush Veterans Administration Medical Center, Indianapolis, Indiana sliangpu@iupui.edu.
Suthat
S
Liangpunsakul
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D000431:Ethanol; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D034622:RNA Interference; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism; D000084622:Sestrins
D055372:AMP-Activated Protein Kinases; D000431:Ethanol; D006360:Heat-Shock Proteins; D008869:Microtubule-Associated Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D014280:Triglycerides; C480860:Map1lc3b protein, mouse; C485523:SESN3 protein, human; D000084622:Sestrins; C549101:Sesn3 protein, mouse
Sestrin3; alcohol; steatosis