{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:20:30Z","timestamp":1790839230652,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2022,9,4]],"date-time":"2022-09-04T00:00:00Z","timestamp":1662249600000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,9]]},"abstract":"\n Abstract<\/jats:title>\n \n Obesity\u2010associated insulin resistance plays a major role in the pathogenesis of non\u2010alcoholic fatty liver disease (NAFLD). The accumulation of diacylglycerol (DAG), ceramides and inflammation are key factors that cause NAFLD. In recent years, the ketogenic diet (KD) has emerged as an effective non\u2010pharmacological intervention for the treatment of NAFLD and other obesity\u2010related metabolic disorders. What remains undetermined is how the KD affects DAG and ceramide content and insulin sensitivity in the liver. Thus, this research was designed to assess these variables, as well as glucose and fat metabolism and markers of inflammation in livers of rats exposed for 8\u00a0weeks to one of the following diets: standard chow (SC), obesogenic high\u2010fat, sucrose\u2010enriched diet (HFS) or a KD. Despite having a higher fat content than the HFS diet, the KD did not cause steatosis and preserved hepatic insulin signalling. The KD reduced DAG content and protein kinase C\u2010\u03b5 activity, but markedly increased liver ceramide content. However, whereas the KD increased ceramide synthase 2 (\n CerS2<\/jats:italic>\n ) expression, it suppressed\n CerS6<\/jats:italic>\n expression, an effect that promoted the production of beneficial very long\u2010chain ceramides instead of harmful long\u2010chain ceramides. The KD also enhanced the liver expression of key genes involved in mitochondrial biogenesis and fatty acid oxidation (\n Pgc\u20101\u03b1<\/jats:italic>\n and\n Fgf21<\/jats:italic>\n ), suppressed inflammatory genes (\n Tnf\u03b1<\/jats:italic>\n ,\n Nf\u2010kb<\/jats:italic>\n ,\n Tlr4<\/jats:italic>\n and\n Il6<\/jats:italic>\n ), and shifted substrate away from\n de novo<\/jats:italic>\n lipogenesis. Thus, through multiple mechanisms the KD exerted anti\u2010steatogenic and insulin\u2010sensitizing effects in the liver, which supports the use of this dietary intervention to treat NAFLD.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n The accumulation of diacylglycerol (DAG), ceramides and inflammation are key factors that cause insulin resistance and non\u2010alcoholic fatty liver disease (NAFLD). This study provides evidence that a ketogenic diet (KD) rich in fat and devoid of carbohydrate reduced DAG content and preserved insulin signalling in the liver.<\/jats:p>\n <\/jats:list-item>\n \n The KD shifted metabolism away from lipogenesis by enhancing genes involved in mitochondrial biogenesis and fatty acid oxidations in the liver.<\/jats:p>\n <\/jats:list-item>\n \n The KD also promoted the production of beneficial very long\u2010chain ceramides instead of potentially harmful long\u2010chain ceramides.<\/jats:p>\n <\/jats:list-item>\n \n Through multiple mechanisms, the KD exerted anti\u2010steatogenic and insulin\u2010sensitizing effects in the liver, which supports the use of this dietary intervention to treat NAFLD.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n 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