Abstract
The ketogenic diet (KD), a high-lipid and low-carbohydrate diet, has been used in the treatment of epilepsy, neurodegenerative disorders, inborn errors of metabolism and cancer; however, the exact mechanism/s of its therapeutic effect is not completely known. We hypothesized that sirtuins (SIRT)—a group of seven NAD-dependent enzymes and important regulators of energy metabolism may be altered under KD treatment. HT22 hippocampal murine neurons were incubated with two important KD metabolites–beta-hydroxybutyrate (BHB) (the predominant ketone body) and decanoic acid (C10), both accumulating under KD. Enzyme activity, protein, and gene expressions of SIRT 1-4, enzyme capacities of the mitochondrial respiratory chain complexes (MRC), citrate synthase (CS) and gene expression of monocarboxylate transporters were measured in control (untreated) and KD-treated cells. Incubation with both–BHB and C10 resulted in significant elevation of SIRT1 enzyme activity and an overall upregulation of the MRC. C10 incubation showed prominent increases in maximal activities of complexes I + III and complex IV of the MRC and ratios of their activities to that of CS, pointing towards a more efficient functioning of the mitochondria in C10-treated cells.
Highlights
Ketogenic Diet: The term “Ketogenic Diet” (KD) was introduced by Dr Wilder at the Mayo clinic in the early 1920s, wherein a ketonemia-producing diet was designed to treat patients with epilepsy.This diet was widely used for several years, but with the introduction of diphenylhydantoin in 1938, the research focus shifted from a ketogenic diet to pharmacological antiepileptic compounds [1]
KD has been successfully used as a therapeutic option in epilepsy [1,2], other neurological disorders [5,9,65], inborn errors of metabolism [66] as well as in cancer [10]; the mechanism underlying these clinical benefits is still unclear
Mitochondrial dysfunction has been shown to be involved in the pathogenesis of epilepsy [67,68], neurodegenerative disorders [69,70], inborn errors of metabolism [58,71,72] and cancer [73]
Summary
Ketogenic Diet: The term “Ketogenic Diet” (KD) was introduced by Dr Wilder at the Mayo clinic in the early 1920s, wherein a ketonemia-producing diet was designed to treat patients with epilepsy. This diet was widely used for several years, but with the introduction of diphenylhydantoin in 1938, the research focus shifted from a ketogenic diet to pharmacological antiepileptic compounds [1]. A novel diet producing an effective ketonemia, termed as the “Medium Chain Triglyceride” (MCT). KD is used as a therapeutic option in mitochondrial disorders such as Complex I deficiency [7], glycogen storage disease type 3 [8], neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease [9], as well as cancer [10]
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