Molecular Regulation of Ketogenesis

In this chapter I discuss the molecular effects of changes in the diet on liver and brain metabolic fuel adaptation, with special reference to ketogenesis and the anticonvulsant ketogenic diet (KD). I examine metabolic adaptation in terms of the effects of dietimposed blood hormone and fuel switches on metabolism of fatty acids, amino acids, and sugars, with special attention to the regulation of activity of multiple enzymes of intermediary metabolic pathways by metabolic sensor proteins. As an example of the effect of dietary change on genetic programming, I examine the regulation of a gene encoding the key enzyme of the ketogenic pathway. In the context of the antiepileptic action of the KD and the structural organization of brain cells, I discuss recent work indicating that the brain possesses both functional fuel sensors and the capacity for localized ketogenesis. Finally, I examine the implications for the anticonvulsant mechanism of the KD of changes in liver and brain ketogenesis and fuel adaptation.