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As a specific activator of nuclear factor E2\u2010related factor 2 (Nrf2), the 4\u2010octyl itaconate (4\u2010OI) has the beneficial effects in antioxidant and anti\u2010inflammation; however, whether 4\u2010OI can alleviate hepatic steatosis and its mechanism is still unknown. The present study was aimed at investigating the protective effects of 4\u2010OI on free fat acid\u2010 (FFA\u2010) induced lipid metabolism disorder and its potential molecular mechanism in hepatocytes. The results showed that 4\u2010OI treatment markedly alleviated FFA\u2010induced oxidative stress and excessive lipid accumulation in hepatocytes. Mechanistically, 4\u2010OI significantly suppressed the overproduction of reactive oxygen species (ROS) through activation of Nrf2; the downregulation of ROS level induced a downregulation of AMP\u2010dependent protein kinase (AMPK) phosphorylation level which finally ameliorated excessive lipid accumulation in FFA\u2010stimulated hepatocytes. In general, our data demonstrated that 4\u2010OI relieves the oxidative stress and lipid metabolism disorder in FFA\u2010stimulated hepatocytes; and these beneficial effects were achieved by activating the Nrf2\u2010AMPK signaling pathway. These data not only expand the new biological function of 4\u2010OI but also provide a theoretical basis for 4\u2010OI to protect against lipid metabolism disorders and related diseases, such as NAFLD.<\/jats:p>","DOI":"10.1155\/2022\/5180242","type":"journal-article","created":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T22:50:07Z","timestamp":1645224607000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["4\u2010Octyl Itaconate Prevents Free Fatty Acid\u2010Induced Lipid Metabolism Disorder through Activating Nrf2\u2010AMPK Signaling Pathway in Hepatocytes"],"prefix":"10.1155","volume":"2022","author":[{"given":"Xu","family":"Chu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longlong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyuan","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6706-0580","authenticated-orcid":false,"given":"Haitian","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,2,18]]},"reference":[{"key":"e_1_2_10_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2020.101122"},{"key":"e_1_2_10_2_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.01.052"},{"key":"e_1_2_10_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0104-9"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2017.08.001"},{"key":"e_1_2_10_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.13264"},{"key":"e_1_2_10_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.05.013"},{"key":"e_1_2_10_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.10.033"},{"key":"e_1_2_10_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.26.1.221-229.2006"},{"key":"e_1_2_10_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2018.02.010"},{"key":"e_1_2_10_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10189"},{"key":"e_1_2_10_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R900010200"},{"key":"e_1_2_10_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1728-5"},{"key":"e_1_2_10_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.002579"},{"key":"e_1_2_10_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.08.064"},{"key":"e_1_2_10_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2017.91"},{"key":"e_1_2_10_16_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.17.1.77"},{"key":"e_1_2_10_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature25986"},{"key":"e_1_2_10_18_2","article-title":"SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate","volume":"11","author":"Olagnier D.","year":"2019","journal-title":"Nature Communications"},{"key":"e_1_2_10_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31147"},{"key":"e_1_2_10_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-02987-9"},{"key":"e_1_2_10_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13078-5"},{"key":"e_1_2_10_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0052-z"},{"key":"e_1_2_10_23_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-018-0294-2"},{"key":"e_1_2_10_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2021.01.020"},{"key":"e_1_2_10_25_2","article-title":"The Cell-Permeable Derivative of the Immunoregulatory Metabolite Itaconate, 4-Octyl Itaconate, Is Anti-Fibrotic in Systemic Sclerosis","volume":"10","author":"Henderson J.","year":"2013","journal-title":"Cells"},{"key":"e_1_2_10_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.06.025"},{"key":"e_1_2_10_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.03.009"},{"key":"e_1_2_10_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2006.11.004"},{"key":"e_1_2_10_29_2","doi-asserted-by":"publisher","DOI":"10.1042\/CS20030326"},{"key":"e_1_2_10_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jff.2021.104437"},{"key":"e_1_2_10_31_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.0c04648"},{"key":"e_1_2_10_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2021.03.034"},{"key":"e_1_2_10_33_2","doi-asserted-by":"crossref","unstructured":"KrssakM. 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