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The present study investigated the mechanisms of high-fat diet (HFD) and CS, individually and in combination, on the pathogenesis of NASH in mice. C57BL\/6 male mice were subjected to either a low-fat chow (CH) or HFD with or without mainstream CS-exposure (4 cigarettes\/day, 5 days\/ week for 14 weeks). HFD alone caused hepatosteatosis (2.5-fold increase in TG content) and a significant increase in 3-nitrotyrisine (by \u223c40-fold) but without an indication of liver injury, inflammation or fibrosis. CS alone in CH-fed mice increased in Tnf\u03b1 expression and macrophage infiltration by 2-fold and relatively less increase in 3-nitrotyrosine (18-fold). Combination of HFD and CS precipitated hepatosteatosis to NASH reflected by exacerbated makers of liver inflammation and fibrosis which were associated with much severe liver oxidative stress (90-fold increase in 3-nitrotyrisine along with 6-fold increase in carbonylated proteins and 56% increase in lipid oxidations). Further studies were performed to administer the antioxidant tempol to CS exposed HFD mice and the results showed that the inhibition of liver oxidative stress prevented inflammatory and fibrotic changes in liver despite persisting hepatosteatosis. Our findings suggest that oxidative stress is a key mechanism underlying CS-promoted progression of simple hepatosteatosis to NASH. Targeting hepatic oxidative stress may be a viable strategy in halting the progression of metabolic associated fatty liver disease.<\/jats:p>","DOI":"10.1042\/cs20210628","type":"journal-article","created":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T09:49:25Z","timestamp":1629798565000},"page":"2103-2119","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Exposure to cigarette smoke precipitates simple hepatosteatosis to NASH in high-fat diet fed mice by inducing oxidative stress"],"prefix":"10.1042","volume":"135","author":[{"given":"Sherouk","family":"Fouda","sequence":"first","affiliation":[{"name":"School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anwar","family":"Khan","sequence":"additional","affiliation":[{"name":"School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley\u00a0M.H.","family":"Chan","sequence":"additional","affiliation":[{"name":"School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Mahzari","sequence":"additional","affiliation":[{"name":"School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia"},{"name":"Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha 65527, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiu","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng\u00a0Xue","family":"Qin","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8443-7071","authenticated-orcid":false,"given":"Ross","family":"Vlahos","sequence":"additional","affiliation":[{"name":"School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3983-0098","authenticated-orcid":false,"given":"Ji-Ming","family":"Ye","sequence":"additional","affiliation":[{"name":"School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2021,9,6]]},"reference":[{"key":"2021113011233573300_B1","doi-asserted-by":"publisher","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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