| Fatty liver disease is tightly associated with several components of the metabolic syndrome, including type2diabetes and obesity. Missense mutation in human KLF11(MODY7gene) leads to diabetes development due to impaired insulin synthesis in pancreas. However, the role of KLF11in peripheral tissues is largely unknown. Here, we show that the expression of the transcription factor KLF11is dysregulated in the livers of diabetic and high-fat (HF) diet-induced obese (DIO) mice. Adenovirus-mediated overexpression of KLF11in the livers of db/db mice and DIO mice activates the PPARa signaling pathway, subsequently markedly improving the fatty liver phenotype. Overexpression of KLF11in db/db mice livers also inhibits the expression of lipogenic genes (SREBP-lc, FAS and ACC) and gluconeogenic genes (PGC-1a, PEPCK and G6pase), thereby lowering blood glucose levels and improving glucose intolerance and insulin sensitivity. Conversely, liver-specific knockdown of KLF11in normal mice increases hepatic triglyceride (TG) levels, owing to decreased fatty liver oxidation, and impairs glucose tolerance and insulin tolerance. Moreover, the treatment of diabetic mice with Ad-shPPARa abolishes the KLF11stimulatory effects on expression of genes involved in fatty acid oxidation and inhibitory effects on hepatic TG content. Meanwhile, the treatment of DIO mice with a PPARa antagonist also achieves the same results. In contrast, PPARa rescue restores the increased hepatic TG levels in KLF11-deficient mice to normal levels. Our data suggest a critical role for KLF11in the regulation of hepatic glucose and lipid metabolism. This study provides a novel target for the treatment of fatty liver and metabolic syndrome. |
