SIRT3, a member of the sirtuin family of NAD+-dependent deacetylase enzymes, has been shown to directly regulate the activity of a range of mitochondrial proteins, suggesting a key role for this enzyme in energy metabolism. Decreased levels of SIRT3 and hyperacetylation of hepatic mitochondrial proteins have been observed in mice fed high-fat diets (HFD). Recent studies also show that SIRT3 knockout mice display accelerated development of the metabolic syndrome on a long-term HFD¹ . Given the detrimental effects of SIRT3 deletion, the aim of this study was to determine if hepatic overexpression of SIRT3 is protective against metabolic defects induced by HFD in mice.
C57BL6 mice were subjected to hydrodynamic tail vein injection of plasmid containing either hSIRT3-FLAG, or empty vector, to produce specific overexpression in the liver. Mice were then maintained on either a chow or HFD for 3 weeks. Liver SIRT3 mRNA, assessed by real-time PCR, was increased in SIRT3-FLAG mice over control (4.6 vs. 39.7 AU, p<0.001). Overexpression of SIRT3 protein was evident by western blot with an additional band above the endogenous mSIRT3 protein, corresponding to human SIRT3-FLAG. At 3 weeks, control mice fed the HFD exhibited a 2.5-fold (p<0.01) increase in the mass of the epididymal fat pad, and displayed a significant impairment in glucose tolerance assessed by intraperitoneal glucose tolerance test (2g/kg). Furthermore, liver triglyceride levels were significantly higher in HFD groups (8.5 vs. 17.6 mmol/g, p<0.01). Despite high overexpression at the mRNA and protein level, SIRT3-FLAG mice displayed similar impairments as control animals in glucose tolerance and triglyceride accumulation in response to the HFD.
While previous studies in SIRT3 knockout animals exhibit detrimental metabolic effects, current results suggest that acute overexpression of SIRT3 in mouse liver in vivo does not protect against hepatic lipid accumulation and glucose intolerance induced by HFD.