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We previously demonstrated that sesaminol increases thermogenesis in adipocytes, improves insulin sensitivity, and mitigates obesity in mice. In this study, we demonstrated that sesaminol increased mitochondrial activity and reduced ROS production in hepatocytes. Therefore, we delve into the metabolic action of sesaminol in obesity\u2010induced NAFLD or metabolic dysfunction\u2010associated liver disease (MAFLD). Here, we report that sesaminol induces OXPHOS proteins and mitochondrial function in\u00a0vivo. Further, our data suggest that sesaminol administration reduces hepatic triacylglycerol accumulation and LDL\u2010C levels. Prominently, the lipidomics analyses revealed that sesaminol administration decreased the major phospholipids such as PC, PE, PI, CL, and PS to maintain membrane lipid homeostasis in the liver upon HFD challenge. Besides, SML reduced ePC and SM molecular species and increased PA levels in the HFD\u2010fed mice. Also, sesaminol renders anti\u2010inflammatory properties and dampens fibrosis markers in the liver. Remarkably, SML lowers the hepatic levels of ALT and AST enzymes and alleviates NAFLD in diet\u2010induced obese mice. The molecular docking analysis identifies peroxisome proliferator\u2010activated receptors as potential endogenous receptors for sesaminol. Together, our study demonstrates plant lignan sesaminol as a potential small molecule that alters the molecular species of major phospholipids, including sphingomyelin and ether\u2010linked PCs in the liver tissue, improves metabolic parameters, and alleviates obesity\u2010induced fatty liver disease in mice.<\/jats:p>","DOI":"10.1096\/fj.202400412rr","type":"journal-article","created":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T10:49:05Z","timestamp":1721645345000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Sesaminol alters phospholipid metabolism and alleviates obesity\u2010induced\n                    <scp>NAFLD<\/scp>"],"prefix":"10.1096","volume":"38","author":[{"given":"Rajprabu","family":"Rajendran","sequence":"first","affiliation":[{"name":"Department of Developmental Biology and Genetics Indian Institute of Science  Bengaluru Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanskriti","family":"Suman","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology and Genetics Indian Institute of Science  Bengaluru Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumya Jaya","family":"Divakaran","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology and Genetics Indian Institute of Science  Bengaluru Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahu","family":"Swatikrishna","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology and Genetics Indian Institute of Science  Bengaluru Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Purnima","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology and Genetics Indian Institute of Science  Bengaluru Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashi","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology and Genetics Indian Institute of Science  Bengaluru Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karan","family":"Sagar","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology and Genetics Indian Institute of Science  Bengaluru Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sona","family":"Rajakumari","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology and Genetics Indian Institute of Science  Bengaluru Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(22)00317-X"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.21037\/tp-23-123"},{"issue":"7","key":"e_1_2_10_4_1","article-title":"The Prospect of non\u2010alcoholic fatty liver disease in adult patients with metabolic syndrome: a systematic review","volume":"15","author":"Zohara Z","year":"2023","journal-title":"Cureus"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(98)70599-2"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M074849"},{"issue":"2","key":"e_1_2_10_7_1","article-title":"Discordant hepatic fatty acid oxidation and triglyceride hydrolysis leads to liver disease. 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