title: Reduction of oxidative stress attenuates lipoapoptosis exacerbated by hypoxia in human hepatocytes.
abstract: Chronic intermittent hypoxia, a characteristic of obstructive sleep apnea (OSA), is associated with the progression of simple hepatic steatosis to necroinflammatory hepatitis. We determined whether inhibition of a hypoxia-induced signaling pathway could attenuate hypoxia-exacerbated lipoapoptosis in human hepatocytes. The human hepatocellular carcinoma cell line (HepG2) was used in this study. Palmitic acid (PA)-treated groups were used for two environmental conditions: Hypoxia (1% O2) and normoxia (20% O2). Following the treatment, the cell viability was determined by the 3,4-(5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay, and the mechanism of lipoapoptosis was evaluated by Western blotting. Hypoxia exacerbated the suppression of hepatocyte growth induced by palmitic acid via activation of mitochondrial apoptotic pathways as a result of endoplasmic reticulum (ER) and oxidative stresses. Ammonium pyrrolidine dithiocarbamate, a scavenger of reactive oxygen species, attenuated the hypoxia-exacerbated lipoapoptosis in hepatocytes, whereas glycerol, which reduces ER stress, did not. This may have been because inhibition of oxidative stress decreases the expression of pro-apoptotic proteins, such as caspase 9 and cytochrome c. These results suggested that modulation of apoptotic signaling pathways activated by oxidative stress can aid in identifying novel therapeutic strategies for the treatment of nonalcoholic steatohepatitis (NASH) with OSA. Further in vivo studies are necessary to understand the pathophysiologic mechanism of NASH with OSA and to prove the therapeutic effect of the modulation of the signaling pathways.
authors: Department of Internal Medicine and Gastrointestinal Cancer Center, Dongnam Institute of Radiological & Medical Sciences, Busan KS012, Korea. mongmani@hanmail.net.
authors: Sang Youn
authors: SY
authors: Hwang
authors: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul KS013, Korea. ydoctor2@hanmail.net.
authors: Su Jong
authors: SJ
authors: Yu
authors: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul KS013, Korea. pindra@empal.com.
authors: Jeong-Hoon
authors: JH
authors: Lee
authors: Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul KS013, Korea. ivtec@naver.com.
authors: Hwi Young
authors: HY
authors: Kim
authors: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul KS013, Korea. yoonjun@sun.ac.kr.
authors: Yoon Jun
authors: YJ
authors: Kim
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D050356:Lipid Metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019308:Palmitic Acid
references: J Biol Chem. 2001 Apr 27;276(17):13935-40
references: 11278723
references: Hepatology. 2007 Apr;45(4):1007-13
references: 17393512
references: J Biol Chem. 2002 Apr 5;277(14):12343-50
references: 11805088
references: Nature. 2000 Jan 6;403(6765):98-103
references: 10638761
references: Apoptosis. 2009 Mar;14(3):309-19
references: 19184438
references: J Biomed Sci. 2009;16:35
references: 19317920
references: Biochim Biophys Acta. 2008 Nov;1782(11):621-6
references: 18801427
references: Liver Int. 2008 Sep;28(8):1080-6
references: 18647236
references: J Cell Biochem. 2014 Jun;115(6):1147-58
references: 24402912
references: Mutat Res. 2005 Jan 6;569(1-2):29-63
references: 15603751
references: Ann Hepatol. 2007 Oct-Dec;6(4):281-3
references: 18007563
references: Hepatology. 2011 May;53(5):1526-37
references: 21520168
references: Hepatology. 2010 Nov;52(5):1836-46
references: 21038418
references: Hepatology. 2005 Jun;41(6):1290-6
references: 15915459
references: Am J Respir Crit Care Med. 2014 Jan 1;189(1):66-76
references: 24256086
references: Obes Rev. 2013 May;14(5):417-31
references: 23387384
references: J Gastroenterol Hepatol. 2009 May;24(5):830-40
references: 19207680
references: J Cell Sci. 2004 Sep 1;117(Pt 19):4461-8
references: 15316071
references: Dig Liver Dis. 2015 Mar;47(3):181-90
references: 25739820
references: Hepatology. 2006 Feb;43(2 Suppl 1):S99-S112
references: 16447287
references: J Clin Biochem Nutr. 2009 Nov;45(3):335-40
references: 19902025
references: Science. 2000 Jan 28;287(5453):664-6
references: 10650002
references: World J Gastroenterol. 2007 Sep 14;13(34):4539-50
references: 17729403
references: Gastroenterology. 1998 Apr;114(4):842-5
references: 9547102
references: Dig Dis Sci. 2005 Dec;50(12):2338-43
references: 16416185
references: Apoptosis. 2002 Aug;7(4):335-45
references: 12101393
references: Sleep. 2009 Apr;32(4):447-70
references: 19413140
references: Semin Liver Dis. 2008 Nov;28(4):360-9
references: 18956292
references: J Hepatol. 2009 Aug;51(2):371-9
references: 19501928
references: Semin Liver Dis. 2008 Nov;28(4):339-50
references: 18956290
references: EMBO Rep. 2001 Mar;2(3):222-8
references: 11266364
references: Toxicol In Vitro. 2006 Dec;20(8):1331-42
references: 16809017
references: Mol Cell Biol. 1996 Aug;16(8):4273-80
references: 8754828
references: Semin Liver Dis. 2001;21(1):43-55
references: 11296696