Hepatic Ketogenic Insufficiency Reprograms Hepatic Glycogen Metabolism and the Lipidome

d'Avignon, D.A.; Puchalska, P.; Ercal, B.; et al. 

In this article, the authors use metabolomics and stable isotope tracers in animals to reveal an unexpected relationship between ketogenic insufficiency and hepatic glycogen metabolism. They find that when ketogenesis is impaired in mice by knocking down 3-hydroxymethylglutaryl-CoA synthase, hepatic glucose production increased by more than 60% in the fed state. This increase in glucose production was fueled by breaking down glycogen. Additionally, the authors show that bis(monoacylglycero)phosphates accumulate in the livers of fed animals with ketogenic insufficiency. These lipids, which also accumulated in mouse models of nonalcoholic fatty liver disease (NAFLD), may represent a generalized biomarker for NAFLD progression.