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We explored whether extracellular superoxide dismutase (EC-SOD) activates adenosine monophosphate-activated protein kinase (AMPK) to enhance antioxidant synthesis and lipid metabolism in NAFLD. Human recombinant EC-SOD (hEC-SOD) was administered to 8-week-old male C57BLKS\/J db\/db mice through intraperitoneal injection once a week for 8 weeks. Target molecules involved in oxidative stress and lipid metabolism were investigated. hEC-SOD improved insulin resistance and systemic and hepatic oxidative stress characterized by increases in urinary 8-hydroxy-deoxyguanosine and 8-isoprostane levels in db\/db mice and a decrease in DHE expression in the liver, respectively. Hepatic SOD3 expression in db\/db mice was reversed by hEC-SOD, which improved hepatic steatosis, inflammation with M2 polarization, apoptosis, autophagy, fibrosis and lipid metabolism in db\/db mice, as reflected by the changes in serum and hepatic markers, monocyte chemoattractant protein-1, tumor necrosis factor-\u03b1, TUNEL-positive cells, Bcl-2\/BAX ratio, beclin1 and LC3-II\/LC3-1. At the molecular level, hEC-SOD increased phosphorylated-AMPK related to CaMKK\u00df, activation of peroxisome proliferative-activated receptor-gamma coactivator (PGC)-1\u03b1 and dephosphorylation of forkhead box O (FoxO)1 and their subsequent downstream signaling. In HepG2Cs cells using AMPK\u03b11 and AMPK\u03b12 siRNA, hEC-SOD demonstrated a protective effect via the direct activation of both AMPK-PGC-1\u03b1 and AMPK-FoxO1. EC-SOD might be a potential therapeutic agent for NAFLD through the activation of AMPK-PGC-1\u03b1 and AMPK-FoxO1 signaling in hepatocytes, which modulates lipid metabolism, leading to anti-inflammatory, antioxidative and antiapoptotic effects and improving autophagy in the liver.<\/jats:p>","DOI":"10.3390\/antiox12122040","type":"journal-article","created":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T03:43:59Z","timestamp":1700797439000},"page":"2040","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Extracellular Superoxide Dismutase Attenuates Hepatic Oxidative Stress in Nonalcoholic Fatty Liver Disease through the Adenosine Monophosphate-Activated Protein Kinase Activation"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5421-6868","authenticated-orcid":false,"given":"Heechul","family":"Nam","sequence":"first","affiliation":[{"name":"Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Lim","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sae-Jong","family":"Oum","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Department of Medicine, School of Medicine, St. George\u2019s University, St. George 11739, Grenada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1727-7842","authenticated-orcid":false,"given":"Si","family":"Bae","sequence":"additional","affiliation":[{"name":"Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheol","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Institute for Aging and Metabolic Diseases, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/nrgastro.2016.147","article-title":"NAFLD and diabetes mellitus","volume":"14","author":"Tilg","year":"2017","journal-title":"Nat. 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