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Microcystin-LR (MC-LR) is a hepatotoxic cyanotoxin which has been reportedly to cause lipid metabolism disorder. In this study, C57BL\/6J mice were fed a high-fat diet (HFD) for eight weeks to build obese an animal model, and subsequently, the obese mice were fed MC-LR for another eight weeks, and we aimed to determine how MC-LR exposure affects the liver lipid metabolism in high-fat-diet-induced obese mice. The results show that MC-LR increased the obese mice serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), indicating damaged liver function. The lipid parameters include serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and liver TG, which were all increased, whilst the high-density lipoprotein cholesterol (HDL-c) was decreased. Furthermore, after MC-LR treatment, histopathological observation revealed that the number of red lipid droplets increased, and that steatosis was more severe in the obese mice. In addition, the lipid synthesis-related genes were increased and the fatty acid \u03b2-oxidation-related genes were decreased in the obese mice after MC-LR exposure. Meanwhile, the protein expression levels of phosphorylation phosphatidylinositol 3-kinase (p-PI3K), phosphorylation protein kinase B (p-AKT), phosphorylation mammalian target of rapamycin (p-mTOR), and sterol regulatory element binding protein 1c (SREBP1-c) were increased; similarly, the p-PI3K\/PI3K, p-AKT\/AKT, p-mTOR\/mTOR, and SREBP1\/\u03b2-actin were significantly up-regulated in obese mice after being exposed to MC-LR, and the activated PI3K\/AKT\/mTOR\/SREBP1 signaling pathway. In addition, MC-LR exposure reduced the activity of superoxide dismutase (SOD) and increased the level of malondialdehyde (MDA) in the obese mice\u2019s serum. In summary, the MC-LR could aggravate the HFD-induced obese mice liver lipid metabolism disorder by activating the PI3K\/AKT\/mTOR\/SREBP1 signaling pathway to hepatocytes, increasing the SREBP1-c-regulated key enzymes for lipid synthesis, and blocking fatty acid \u03b2-oxidation.<\/jats:p>","DOI":"10.3390\/toxins14120833","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T07:38:50Z","timestamp":1669793930000},"page":"833","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":104,"title":["MC-LR Aggravates Liver Lipid Metabolism Disorders in Obese Mice Fed a High-Fat Diet via PI3K\/AKT\/mTOR\/SREBP1 Signaling Pathway"],"prefix":"10.3390","volume":"14","author":[{"given":"Hanyu","family":"Chu","sequence":"first","affiliation":[{"name":"Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, University of South China, Hengyang 421001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Du","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yang","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangling","family":"Feng","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lemei","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Public Health, Changsha Medical University, Changsha 410219, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2268-6050","authenticated-orcid":false,"given":"Jihua","family":"Chen","sequence":"additional","affiliation":[{"name":"Xiangya School of Public Health, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5687-0556","authenticated-orcid":false,"given":"Fei","family":"Yang","sequence":"additional","affiliation":[{"name":"Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, University of South China, Hengyang 421001, China"},{"name":"Xiangya School of Public Health, Central South University, Changsha 410078, China"},{"name":"The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province, Department of Education, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4077","DOI":"10.1007\/s11695-019-04200-z","article-title":"Updates on Monogenic Obesity in a Multifactorial Disease","volume":"29","author":"Baxter","year":"2019","journal-title":"Obes. 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