The ketogenic diet prevents steatosis and insulin resistance by reducing lipogenesis, diacylglycerol accummulation, and PKC activity in male rat liver.

Obesity-associated insulin resistance plays a major role in the pathogenesis of nonalcoholic 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-pharmacological intervention for the treatment of NAFLD and other obesity-related metabolic disorders. What remains undetermined is how the KD affects DAG and ceramides 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 weeks to one of the following diets: standard chow (SC), obesogenic high-fat, sucrose-enriched 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 epsilon (PKCε) activity, but markedly increased liver ceramides content. However, whereas the KD increased ceramide synthase 2 (CerS2) expression, it suppressed CerS6 expression, an effect that promoted the production of beneficial very long-chain ceramides instead of harmful long-chain ceramides. The KD also enhanced the liver expression of key genes involved in mitochondrial biogenesis and fatty acid oxidation (Pgc-1α and Fgf21), suppressed inflammatory genes (Tnfα, Nf-kb, Tlr4, and Il6), and shifted substrate away from de-novo lipogenesis. Thus, through multiple mechanisms the KD exerted anti-steatogenic and insulin-sensitizing effects in the liver, which supports the use of this dietary intervention to treat NAFLD. Abstract figure legend This article is protected by copyright. All rights reserved.