SIRT6 regulates SREBP1c-induced glucolipid metabolism in liver and pancreas via the AMPKα-mTORC1 pathway.

The aim of this study was to determine the mechanism by which SIRT6 regulates glucolipid metabolism disorders. We detected histological and molecular changes in Sprague-Dawley rats as well as in BRL 3A and INS-1 cell lines subjected to overnutrition and starvation. SIRT6, SREBP1c, and glucolipid metabolism biomarkers were identified by fluorescence co-localization, real-time PCR, and western blotting. Gene silencing studies were performed. Recombinant SIRT6, AMPK agonist (AICAR), mTOR inhibitor (rapamycin), and liver X receptor (LXR) agonist (T0901317) were used to pre-treated in BRL 3A and INS-1 cells. Real-time PCR and western blotting were used to detect related proteins, and cell counting was utilized to detect proliferation. We obtained conflicting results; SIRT6 and SREBP1c appeared in both the liver and pancreas of high-fat and hungry rats. Recombinant SIRT6 alleviated the decrease in AMPKα and increase in mTORC1 (complex of mTOR, Raptor, and Rheb) caused by overnutrition. SIRT6 siRNA reversed the glucolipid metabolic disorders caused by the AMPK agonist and mTOR inhibitor but not by the LXR agonist. Taken together, our results demonstrate that SIRT6 regulates glycolipid metabolism through AMPKα-mTORC1 regulating SREBP1c in the liver and pancreas induced by overnutrition and starvation, independent of LXR.