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Abstract
Phosphoenolpyruvate carboxykinase 1 (PEPCK1) is the critical enzyme for gluconeogenesis and is linked with type II diabetes. Previous studies have found that SIRT2, a deacetylase, plays an important role in deacetylating PEPCK1 and little is known about the anti-diabetic activity of SIRT2 inhibitors. In this study, we investigated the anti-diabetic effects of sirtinol, a SIRT2 inhibitor, on cell gluconeogenesis in vivo and in vitro. Immunoblotting analysis revealed that sirtinol significantly decreased the protein level of PEPCK1, and was accompanied by the hyperacetylation of PEPCK1 as well as decreased glucose output in a dose-dependent manner. Furthermore, sirtinol exerted little impact on endogenous PEPCK1 levels in SIRT2-knockdown cells. The in vitro experiments further confirmed the in vivo data; sirtinol decreased liver PEPCK1 protein level and prevented pyruvate-induced blood glucose from increasing. Based on our results, the rate-limiting enzyme PEPCK1 is the primary target of sirtinol, and the inhibition of SIRT2 activity may play an important role in cell gluconeogenesis. Thus, SIRT2 may be a novel molecular target for diabetes therapy and may thus shed light on the underlying diabetes treatment mechanisms of sirtinol.
Highlights
Diabetes is a serious worldwide problem threatening the health of millions of people
We discovered that sirtinol-induced acetylation plays a critical role in protein post-translational modification of PEPCK1 and cell gluconeogenesis by targeting SIRT2
Using a eukaryotic purified SIRT2 deacetylated system (Fig. 1B), we found that Lys40-acetylation levels of tubulin and overall-acetylation levels of PEPCK1 were significantly reduced following SIRT2 and its coenzyme treatment
Summary
Diabetes is a serious worldwide problem threatening the health of millions of people. Acetylation, an evolutionarily conserved post-translational modification, has been identified in metabolic enzymes and has played key roles in metabolic regulation[2, 3]. PEPCK1 is an important marker in the evaluation of type II diabetes[4, 5], and plays an important role in gluconeogenesis by catalyzing the first committed and rate-limiting step mainly in the liver, where it maintains glucose homeostasis[6,7,8,9]. Due to the important role of PEPCK1, its regulation has been extensively studied. We discovered that sirtinol-induced acetylation plays a critical role in protein post-translational modification of PEPCK1 and cell gluconeogenesis by targeting SIRT2. The hypoglycemic effects of sirtinol on glucose output and gluconeogenesis were confirmed in vitro as well as in vivo
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