Beneficial Effects of Ketogenic Diet on Nonalcoholic Steatohepatitis in Obese Mice Model

Obesity is associated with a low-grade inflammation, characterized by the secretion of inflammatory mediators, that contribute to non-alcoholic fatty liver disease (NAFLD) development. Steatosis may be complicated by hepatocellular injury and liver inflammation (steatohepatitis or NASH). Ketogenic diet (KD), a high-fat and low-carbohydrate diet, seems to present anti-inflammatory properties which could reduce NAFLD development. However, the mechanisms involved in its beneficial effects remain unclear. Obesity was induced in C57/Bl6 mice (n = 20) by using a high-fat, high-sugar diet (HFD). After 16 weeks of HFD, mice were split into two groups for six weeks: KD mice (n = 10) and HFD mice (n = 10). At the end of the 22-week protocol, we measured liver weight, hepatic lipid accumulation and inflammatory infiltrates with histological staining, and hepatic gene expression by RT-qPCR. Both HFD and KD were isocaloric and compared with a control diet (Ctrl) group of mice (n = 10). After 22 weeks of HFD, mice developed obesity (+82% of weight gain, p < 0.001) associated with an increase in liver weight (+113%, p < 0.001) and hepatic lipid accumulation (+158%, p < 0.001), compared with Ctrl. RT-qPCR revealed an increase in TNFa (p < 0.05), IL-1 (p < 0.05) and collagen 1 (p < 0.01) gene expression, but no changes of IL-10, TGFb and IFNg, compared to Ctrl. Histological staining showed an important steatosis and inflammatory infiltrates. Compared to HFD, six weeks of KD allow to reduce the liver weight (−31%, p < 0.01), reduce steatosis and ballooning hepatocytes, and decreased IL-6 (p < 0.05) and collagen 1 (p < 0.05) gene expression. However, KD had no effect on IL-1, TNFa, IFNg, IL-10 gene expression, compared to HFD. These results suggest that in a context of hypercaloric diet and NAFLD development, replacing sugar by lipids is efficient to prevent the onset of NASH at least partly due to a reduction in lipid accumulation and hepatocellular injuries.