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: Sang Youn Hwang, Su Jong Yu, Jeong-Hoon Lee, Hwi Young Kim, Yoon Jun Kim
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 16 Issue 2 Pg. 3323-34 (Feb 03 2015) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 25654228 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Palmitic Acid

Topics

• Apoptosis
• Cell Line
• Cell Proliferation (drug effects)
• Endoplasmic Reticulum Stress (drug effects)
• Hepatocytes (drug effects, metabolism)
• Humans
• Hypoxia (metabolism)
• Lipid Metabolism
• Mitochondria (drug effects, metabolism)
• Oxidative Stress
• Palmitic Acid (metabolism, pharmacology)
• Signal Transduction (drug effects)