The antianginal ranolazine fails to improve glycaemia in obese liver-specific pyruvate dehydrogenase deficient male mice

AimsRecent studies have demonstrated that stimulating pyruvate dehydrogenase (PDH, gene Pdha1), the rate-limiting enzyme of glucose oxidation, can reverse obesity-induced non-alcoholic fatty liver disease (NAFLD), which can be achieved via treatment with the antianginal ranolazine. Accordingly, our aim was to determine whether ranolazine's ability to mitigate obesity-induced NAFLD and hyperglycaemia requires increases in hepatic PDH activity. MethodsWe generated liver-specific PDH-deficient (Pdha1(Liver-/-)) mice, which were provided a high-fat diet for 12 weeks to induce obesity. Pdha1(Liver-/-) mice and their albumin-Cre (Alb(Cre)) littermates were randomized to treatment with either vehicle control or ranolazine (50 mg/kg) once daily via oral gavage during the final 5 weeks, following which we assessed glucose and pyruvate tolerance. ResultsPdha1(Liver-/-) mice exhibited no overt phenotypic differences (e.g. adiposity, glucose tolerance) when compared to their Alb(Cre) littermates. Of interest, ranolazine treatment improved glucose tolerance and mildly reduced hepatic triacylglycerol content in obese Alb(Cre) mice but not in obese Pdha1(Liver-/-) mice. The latter was independent of changes in hepatic mRNA expression of genes involved in regulating lipogenesis. ConclusionsLiver-specific PDH deficiency is insufficient to promote an NAFLD phenotype. Nonetheless, hepatic PDH activity partially contributes to how the antianginal ranolazine improves glucose tolerance and alleviates hepatic steatosis in obesity.

Automated summary

Recent studies have shown that stimulating the rate-limiting enzyme of glucose oxidation, pyruvate dehydrogenase (PDH), can reverse obesity-induced non-alcoholic fatty liver disease (NAFLD), and this can be achieved with the use of the antianginal drug ranolazine. The aim of this study was to determine if ranolazine's effects on NAFLD and hyperglycaemia require increased hepatic PDH activity.