Reduction of oxidative stress attenuates lipoapoptosis exacerbated by hypoxia in human hepatocytes

Sang Youn Hwang, Su Jong Yu, Jeong Hoon Lee, Hwi Young Kim, Yoon Jun Kim

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4 Scopus citations


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.

Original languageEnglish
Pages (from-to)3323-3334
Number of pages12
JournalInternational Journal of Molecular Sciences
Issue number2
StatePublished - 3 Feb 2015

Bibliographical note

Publisher Copyright:
© 2015 by the authors; licensee MDPI, Basel, Switzerland.


  • Endoplasmic reticulum stress
  • Hypoxia
  • Lipoapoptosis
  • Nonalcoholic steatohepatitis
  • Obstructive sleep apnea
  • Oxidative stress


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