Sestrin1 is involved in the regulation of gluconeogenesis in mouse liver cells

Objective To investigate the role and regulatory mechanism of stress-inducing protein 1(SESN1) in liver gluconeogenesis of fasting mice. Methods RT-qPCR was used to detect mRNA expression of SESN1 in liver tissues of C57BL/6J mice and primary mouse hepatocytes treated with forskolin (Fsk) and dexamethasone(Dex). HepG2 cells were transfected with plasmids and the effects of SESN1 overexpression on mRNA expression of gluconeogenesis related genes PGC-1α, PEPCK and G6Pase was detected by RT-qPCR. The effect of SESN1 on the promoter activity of PGC-1α in HepG2 cells was studied using a dual luciferase reporter system. The effect of SESN1 on PGC-1α deacetylation was detected by overexpression of SESN1 and inhibition of SIRT1 expression.By knocking down SIRT1 expression, we detected whether it mediated the changes in mRNA levels of SESN1 induced gluconeogenesis related genes. Results The mRNA expression of SESN1 was significantly increased in liver tissues of starved C57BL/6J mice and in primary hepatocytes treated with Fsk and Dex(P＜0.001). Over-expression of SESN1 in HepG2 cells promoted mRNA expression of PGC-1α, PEPCK and G6Pase(P＜0.001) and promoter activity of PGC-1α(P＜0.001). Over-expression of SESN1 decreased the acetylation level of PGC-1α in primary hepatocytes.Sirt family inhibitors NAM and shRNA adenovirus interfered with SIRT1 expression respectively, and antagonized the deacetylation effect of SESN1 on PGC-1α. The expression of PGC-1α, PEPCK and G6Pase induced by SIRT1 was also significantly impaired(P＜0.000 1). Conclusions SESN1 regulates liver gluconeogenesis in mice with a SIRT1-dependent mechanism.