{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T17:58:40Z","timestamp":1787680720485,"version":"build-2784847793"},"reference-count":31,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T00:00:00Z","timestamp":1661126400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011882","name":"College of Public Health, University of Nebraska Medical Center","doi-asserted-by":"publisher","award":["Health Innovation grant"],"award-info":[{"award-number":["Health Innovation grant"]}],"id":[{"id":"10.13039\/100011882","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["1P20GM104320-04"],"award-info":[{"award-number":["1P20GM104320-04"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Non-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25\u201330 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>In this work, we generated a mouse model of lean and obese NASH-HCC using a choline deficient\/high trans-fat\/fructose\/cholesterol diet and a choline supplemented\/high trans-fat\/fructose\/cholesterol diet, respectively, to compare progression to NASH-HCC in lean versus obese mice. Comparisons were made at the organismal, histological, and molecular level by investigating fatty acid metabolism in the plasma of these mice.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Obese mice showed more pronounced glucose intolerance and insulin resistance, higher levels of plasma cholesterol and triglycerides, and higher penetrance of NASH compared to lean mice. Despite the abnormal metabolic profile of obese mice, male obese and lean mice developed HCC with similar penetrance (53.3% and 53.8%, respectively), albeit lean mice showed faster tumor progression as evidenced by the larger tumor size and lower HCC-free survival. None of the female lean mice developed HCC, while 50% of female obese mice developed HCC. Both groups of mice showed a reduction in plasma polyunsaturated fatty acids (PUFAs), however, the levels were higher towards the endpoint in obese mice compared to lean mice.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Unhealthy diet composition appears to drive progression to NASH-HCC rather than the organismal effects of obesity. PUFA levels may increase due to systemic inflammation in obese mice and act as suppressors of tumor progression, thus delaying HCC progression in obese mice compared to lean mice. These models could be used to further dissect the molecular pathogenesis of lean and obese NASH-HCC and address the mechanisms whereby PUFAs may be implicated in hepatocarcinogenesis.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0272623","type":"journal-article","created":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T17:33:56Z","timestamp":1661189636000},"page":"e0272623","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":24,"title":["Differential progression of unhealthy diet-induced hepatocellular carcinoma in obese and non-obese mice"],"prefix":"10.1371","volume":"17","author":[{"given":"Emma","family":"Hymel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Vlock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8391-390X","authenticated-orcid":true,"given":"Kurt W.","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4375-5812","authenticated-orcid":true,"given":"Paraskevi A.","family":"Farazi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,8,22]]},"reference":[{"issue":"18","key":"pone.0272623.ref001","doi-asserted-by":"crossref","first-page":"5320","DOI":"10.3748\/wjg.v20.i18.5320","article-title":"Liver transplantation for nonalcoholic fatty liver disease: new challenges and new opportunities","volume":"20","author":"M Shaker","year":"2014","journal-title":"World J Gastroenterol"},{"issue":"4","key":"pone.0272623.ref002","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1002\/cld.710","article-title":"The epidemiology of nonalcoholic steatohepatitis","volume":"11","author":"Z. 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