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Oxidative stress and ER stress induce Zidovudine (AZT)‐mediated hepatic lipid accumulation
Author(s) -
Banerjee Atrayee,
Abdelmegeed Mohamed A,
Jang Sehwan,
Song Byoung Joon
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1144.6
Subject(s) - oxidative stress , zidovudine , lipid peroxidation , lipid metabolism , chemistry , pharmacology , medicine , endocrinology , toxicity , biochemistry , immunology , virus , viral disease
Zidovudine (AZT) was the first drug approved by the U.S. Food and Drug Administration for treating AIDS patients. The clinical effectiveness of AZT is constrained due to its various adverse side effects including hepatotoxicity. However, the mechanism of hepatic lipid accumulation in AZT‐treated individuals is unknown. We hypothesized that AZT‐induced oxidative stress alters the mitochondrial fat oxidation pathway, leading to fat accumulation. Our study showed significant increase in lipid accumulation, inflammation and toxicity in female mice exposed to AZT for 10 days. Markers of oxidative stress such as CYP4A levels, protein oxidation, nitration, glycation and lipid peroxidation were significantly higher in the AZT‐treated mice as compared to the controls. Further, the levels of ER stress marker proteins like GRP78, p‐PERK, and p‐ELF2α were significantly elevated in AZT‐treated mice. In addition, significantly increased levels of nuclear SREBP‐1c and acetyl‐CoA carboxylase along with significant decrease in the levels of phospho‐AMP kinase and PPARα, a key transcription factor for fatty acid oxidation, were observed in AZT‐treated group. Collectively, these data indicate that oxidative stress and ER stress play a critical role in lipid accumulation and hepatotoxicity in AZT‐treated animals. [Support: Intramural Research Program of NIAAA].