The impaired redox balance in peroxisomes of catalase knockout mice accelerates nonalcoholic fatty liver disease through endoplasmic reticulum stress

Inah Hwang, Md Jamal Uddin, Eun Seon Pak, Hyeji Kang, Eun Jung Jin, Suin Jo, Dongmin Kang, Hyukjin Lee, Hunjoo Ha

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Peroxisomes are essential organelles for maintaining the homeostasis of lipids and reactive oxygen species (ROS). While oxidative stress-induced endoplasmic reticulum (ER) stress plays an important role in nonalcoholic fatty liver disease (NAFLD), the role of peroxisomes in ROS-mediated ER stress in the development of NAFLD remains elusive. We investigated whether an impaired peroxisomal redox state accelerates NAFLD by activating ER stress by inhibiting catalase, an antioxidant expressed exclusively in peroxisomes. Wild-type (WT) and catalase knockout (CKO) mice were fed either a normal diet or a high-fat diet (HFD) for 11 weeks. HFD-induced phenotype changes and liver injury accompanied by ER stress and peroxisomal dysfunction were accelerated in CKO mice compared to WT mice. Interestingly, these changes were also significantly increased in CKO mice fed a normal diet. Inhibition of catalase by 3-aminotriazole in hepatocytes resulted in the following effects: (i) increased peroxisomal H2O2 levels as measured by a peroxisome-targeted H2O2 probe (HyPer-P); (ii) elevated intracellular ROS; (iii) decreased peroxisomal biogenesis; (iv) activated ER stress; (v) induced lipogenic genes and neutral lipid accumulation; and (vi) suppressed insulin signaling cascade associated with JNK activation. N-acetylcysteine or 4-phenylbutyric acid effectively prevented those alterations. These results suggest that a redox imbalance in peroxisomes perturbs cellular metabolism through the activation of ER stress in the liver.

Original languageEnglish
Pages (from-to)22-32
Number of pages11
JournalFree Radical Biology and Medicine
Volume148
DOIs
StatePublished - 20 Feb 2020

Keywords

  • Catalase
  • ER stress
  • Hepatocytes
  • Nonalcoholic steatohepatitis
  • Peroxisomal biogenesis
  • Primary cell cultures
  • Reactive oxygen species

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