GLP-1 and incretin mimetics, such as exenatide, have been shown to attenuate hepatocyte steatosis both in vivo and in vitro, while the specific mechanism underlying is unclear. SIRT1, a NAD+-dependent protein deacetylase, has been considered as a crucial regulator in hepatic lipid homeostasis by accumulated studies. Here, we speculate that SIRT1 might mediate the effect of GLP-1 receptor agonist exenatide (exendin-4) on ameliorating hepatic steatosis. After 8-week exenatide treatment in HFD induced male SIRT1+/- mice and their wild-type (WT) littermates, we found that lipid deposition and inflammation in liver, which were improved dramatically in WT group, diminished in SIRT1+/- mice. In addition, the protein expression of SIRT1 and p-AMPK were up-regulated, while lipogenic related protein including SREBP-1c and PNPLA3 were down-regulated in WT group after exenatide treatment. However, none of these changes were observed in SIRT1+/- mice. In HepG2 cells, exendin-4-reversed lipid deposition induced by palmitate was hampered when SIRT1 was silenced by SIRT1 RNAi. Our data demonstrate that SIRT1 mediates the effect of exenatide on ameliorating hepatic steatosis, suggesting GLP-1 receptor agonist could serve as a potential drug for NAFLD, especially in T2DM combined with NAFLD, and SIRT1 could be a therapeutic target of NAFLD.
* Two authors contribute equally to this study.
- Received February 16, 2014.
- Accepted May 19, 2014.
- © 2014 by the American Diabetes Association.
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