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The severity of NAFLD ranges from simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH). Simple steatosis is relatively benign until it progresses to NASH, which is characterised by hepatic injury, inflammation, oxidative stress and fibrosis. Hepatic fibrosis is a risk factor for cirrhosis and primary hepatocellular carcinoma. Our studies have focused on the impact of diet on the onset and progression of NASH. We developed a mouse model of NASH by feeding Ldlr<jats:sup>\u2212\/\u2212<\/jats:sup> mice a western diet (WD), a diet moderately high in saturated and trans-fat, sucrose and cholesterol. The WD induced a NASH phenotype in Ldlr<jats:sup>\u2212\/\u2212<\/jats:sup> mice that recapitulates many of the clinical features of human NASH. We also assessed the capacity of the dietary <jats:italic>n-<\/jats:italic>3 PUFA, i.e. EPA (20 : 5,<jats:italic>n-<\/jats:italic>3) and DHA (22 : 6,<jats:italic>n-<\/jats:italic>3), to prevent WD-induced NASH in Ldlr<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Histologic, transcriptomic, lipidomic and metabolomic analyses established that DHA was equal or superior to EPA at attenuating WD-induced dyslipidemia and hepatic injury, inflammation, oxidative stress and fibrosis. Dietary <jats:italic>n-<\/jats:italic>3 PUFA, however, had no significant effect on WD-induced changes in body weight, body fat or blood glucose. These studies provide a molecular and metabolic basis for understanding the strengths and weaknesses of using dietary <jats:italic>n-<\/jats:italic>3 PUFA to prevent NASH in human subjects.<\/jats:p>","DOI":"10.1017\/s002966511500244x","type":"journal-article","created":{"date-parts":[[2015,8,18]],"date-time":"2015-08-18T06:32:47Z","timestamp":1439879567000},"page":"1-9","update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":32,"title":["Impact of dietary fat on the development of non-alcoholic fatty liver disease in Ldlr<sup>\u2212\/\u2212<\/sup> mice"],"prefix":"10.1017","volume":"75","author":[{"given":"Donald B.","family":"Jump","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher M.","family":"Depner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sasmita","family":"Tripathy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelli A.","family":"Lytle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"56","published-online":{"date-parts":[[2015,8,18]]},"reference":[{"key":"S002966511500244X_ref9","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)67402-8"},{"key":"S002966511500244X_ref34","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22584"},{"key":"S002966511500244X_ref43","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-nutr-071812-161139"},{"key":"S002966511500244X_ref27","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/212865"},{"key":"S002966511500244X_ref67","doi-asserted-by":"publisher","DOI":"10.1016\/j.clnu.2011.12.007"},{"key":"S002966511500244X_ref10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2011.04724.x"},{"key":"S002966511500244X_ref73","doi-asserted-by":"publisher","DOI":"10.1177\/1756283X11413002"},{"key":"S002966511500244X_ref46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2012.03.004"},{"key":"S002966511500244X_ref31","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R008896"},{"key":"S002966511500244X_ref24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.2011.06957.x"},{"key":"S002966511500244X_ref101","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2007.12.003"},{"key":"S002966511500244X_ref105","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.12556"},{"key":"S002966511500244X_ref102","doi-asserted-by":"publisher","DOI":"10.1038\/nri1391"},{"key":"S002966511500244X_ref95","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2008.05.056"},{"key":"S002966511500244X_ref98","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-004-0758-8"},{"key":"S002966511500244X_ref99","doi-asserted-by":"publisher","DOI":"10.2337\/db06-1491"},{"key":"S002966511500244X_ref41","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20093"},{"key":"S002966511500244X_ref89","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0b013e32833b257a"},{"key":"S002966511500244X_ref86","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27695"},{"key":"S002966511500244X_ref104","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2009.11.011"},{"key":"S002966511500244X_ref92","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27289"},{"key":"S002966511500244X_ref84","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn.81.2.341"},{"key":"S002966511500244X_ref80","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M050062"},{"key":"S002966511500244X_ref91","doi-asserted-by":"publisher","DOI":"10.1515\/CCLM.2011.020"},{"key":"S002966511500244X_ref83","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00145.2011"},{"key":"S002966511500244X_ref109","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2015.02.006"},{"key":"S002966511500244X_ref81","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/137.7.1776"},{"key":"S002966511500244X_ref65","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.2007.04977.x"},{"key":"S002966511500244X_ref62","doi-asserted-by":"publisher","DOI":"10.1126\/science.12192669"},{"key":"S002966511500244X_ref3","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20973"},{"key":"S002966511500244X_ref59","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2005.04.004"},{"key":"S002966511500244X_ref49","doi-asserted-by":"publisher","DOI":"10.3945\/jn.112.158865"},{"key":"S002966511500244X_ref44","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v17.i29.3377"},{"key":"S002966511500244X_ref94","unstructured":"US National Institute of health (2015) NAFLD, NASH and omega-3 fatty acids. http:\/\/www.clinicaltrials.gov. 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