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

AIMS

Recent 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.

METHODS

We generated liver-specific PDH-deficient (Pdha1 ) mice, which were provided a high-fat diet for 12 weeks to induce obesity. Pdha1 mice and their albumin-Cre (Alb ) 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.

RESULTS

Pdha1 mice exhibited no overt phenotypic differences (e.g. adiposity, glucose tolerance) when compared to their Alb littermates. Of interest, ranolazine treatment improved glucose tolerance and mildly reduced hepatic triacylglycerol content in obese Alb mice but not in obese Pdha1 mice. The latter was independent of changes in hepatic mRNA expression of genes involved in regulating lipogenesis.

CONCLUSIONS

Liver-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.