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Skatole has an anti-lipid peroxidation effect and is a biomarker for several diseases. However, its effect on hepatocyte lipid metabolism and lipotoxicity has not been elucidated. Hepatic lipotoxicity is induced by excess saturated free fatty acids in hyperlipidemia, which directly damages the hepatocytes. Lipotoxicity is involved in several metabolic diseases and hepatocytes, particularly affecting nonalcoholic fatty liver disease (NAFLD) progression. NAFLD is caused by the accumulation of fat by excessive free fatty acids (FFAs) in the blood and is accompanied by hepatic damage, such as endoplasmic reticulum (ER) stress, abnormal glucose and insulin metabolism, oxidative stress, and lipoapoptosis with lipid accumulation. Hepatic lipotoxicity causes multiple hepatic damages in NAFLD and has a directly effect on the progression from NAFLD to nonalcoholic steatohepatitis (NASH). This study confirmed that the natural compound skatole improves various damages to hepatocytes caused by lipotoxicity in hyperlipidemic conditions. To induce lipotoxicity, we exposed HepG2, SNU-449, and Huh7 cells to palmitic acid, a saturated fatty acid, and confirmed the protective effect of skatole. Skatole inhibited fat accumulation in the hepatocytes, reduced ER and oxidative stress, and recovered insulin resistance and glucose uptake. Importantly, skatole reduced lipoapoptosis by regulating caspase activity. In conclusion, skatole ameliorated multiple types of hepatocyte damage induced by lipotoxicity in the presence of excess free fatty acids.<\/jats:p>","DOI":"10.3390\/nu15061490","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T07:56:37Z","timestamp":1679298997000},"page":"1490","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Natural Product Skatole Ameliorates Lipotoxicity-Induced Multiple Hepatic Damage under Hyperlipidemic Conditions in Hepatocytes"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1398-1226","authenticated-orcid":false,"given":"Sin-Hyoung","family":"Hong","sequence":"first","affiliation":[{"name":"Division of Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of Korea"},{"name":"Department of Bio-Analytical Science, University of Science and Technology, Daejeon 34113, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeonhee","family":"Hong","sequence":"additional","affiliation":[{"name":"Division of Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minji","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of Korea"},{"name":"Department of Bio-Analytical Science, University of Science and Technology, Daejeon 34113, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byeong-Rak","family":"Keum","sequence":"additional","affiliation":[{"name":"Division of Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of Korea"},{"name":"Research Center for Drug Development, CYPHARMA, Daejeon 28119, Republic of Korea"},{"name":"Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0360-4435","authenticated-orcid":false,"given":"Gun-Hwa","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of Korea"},{"name":"Department of Bio-Analytical Science, University of Science and Technology, Daejeon 34113, Republic of Korea"},{"name":"Research Center for Drug Development, CYPHARMA, Daejeon 28119, Republic of Korea"},{"name":"Department of Analytical Science and Technology, Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. 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