Ablation of catalase promotes non-alcoholic fatty liver via oxidative stress and mitochondrial dysfunction in diet-induced obese mice

• Published in: Pflügers Archiv Vol. 471; no. 6; pp. 829 - 843
• Main Authors: Shin, Su-Kyung, Cho, Hyun-Woo, Song, Seung-Eun, Bae, Jae-Hoon, Im, Seung-Soon, Hwang, Inha, Ha, Hunjoo, Song, Dae-Kyu
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2019; Springer Nature B.V
• Subjects: Animals; Antioxidants; Biomedical and Life Sciences; Biomedicine; Catalase; Catalase - metabolism; Cell Biology; Copy number; Cytology; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Fatty liver; Hep G2 Cells; Hepatoma; High fat diet; Human Physiology; Humans; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Integrative Physiology; Lipid Metabolism; Lipid peroxidation; Liver; Liver - metabolism; Liver - ultrastructure; Liver diseases; Male; Melatonin; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Liver - metabolism; Mitochondrial DNA; Molecular Medicine; Neurosciences; Non-alcoholic Fatty Liver Disease - enzymology; Non-alcoholic Fatty Liver Disease - etiology; Obesity - complications; Obesity - enzymology; Oxidative Stress; Receptors; Rodents; Therapeutic applications; ER stress; Oxidative stress; Hydrogen peroxide; Catalase; Non-alcoholic fatty liver disease; Mitochondrial function
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-018-02250-3

Hydrogen peroxide (H 2 O 2 ) produced endogenously can cause mitochondrial dysfunction and metabolic complications in various cell types by inducing oxidative stress. In the liver, oxidative and endoplasmic reticulum (ER) stress affects the development of non-alcoholic fatty liver disease (NAFLD). Although a link between both stresses and fatty liver diseases has been suggested, few studies have investigated the involvement of catalase in fatty liver pathogenesis. We examined whether catalase is associated with NAFLD, using catalase knockout (CKO) mice and the catalase-deficient human hepatoma cell line HepG2. Hepatic morphology analysis revealed that the fat accumulation was more prominent in high-fat diet (HFD) CKO mice compared to that in age-matched wild-type (WT) mice, and lipid peroxidation and H 2 O 2 release were significantly elevated in CKO mice. Transmission electron micrographs indicated that the liver mitochondria from CKO mice tended to be more severely damaged than those in WT mice. Likewise, mitochondrial DNA copy number and cellular ATP concentrations were significantly lower in CKO mice. In fatty acid-treated HepG2 cells, knockdown of catalase accelerated cellular lipid accumulation and depressed mitochondrial biogenesis, which was recovered by co-treatment with N -acetyl cysteine or melatonin. This effect of antioxidant was also true in HFD-fed CKO mice, suppressing fatty liver development and improving hepatic mitochondrial function. Expression of ER stress marker proteins and hepatic fat deposition also increased in normal-diet, aged CKO mice compared to WT mice. These findings suggest that H 2 O 2 production may be an important event triggering NAFLD and that catalase may be an attractive therapeutic target for preventing NAFLD.