Role of KLF15 in regulation of hepatic gluconeogenesis and metformin action.
Role of KLF15 in regulation of hepatic gluconeogenesis and metformin action.
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作者：
Takashima M;Ogawa W;Hayashi K;Inoue H;Kinoshita S;Okamoto Y;Sakaue H;Wataoka Y;Emi A;Senga Y;Matsuki Y;Watanabe E;Hiramatsu R;Kasuga M
新生血管发生率的增加是2型糖尿病患者高血糖的主要原因，二甲双胍的抗糖尿病作用被认为至少部分通过抑制新生血管发生来实现。我们研究了转录因子KLF15是否在糖尿病新生的调节中起作用，以及KLF15是否参与二甲双胍的抗糖尿病作用。在此，我们发现KLF15与转录辅激活因子过氧化物酶体增殖物激活受体γ辅激活因子1α协同调节致突变酶或氨基酸降解酶基因的表达。在糖尿病小鼠中，肝脏特异性消融KLF15导致致血管生成酶或氨基酸分解代谢酶基因表达下调，并改善高血糖。培养的肝细胞暴露于二甲双胍通过加速其降解和下调其mRNA降低了KLF15的丰度。二甲双胍可抑制肝细胞培养物中促凋亡酶或氨基酸降解酶的基因表达，而二甲双胍的这些作用可通过恢复KLF15表达而减弱。二甲双胍给药可抑制肝脏中KLF15的表达和葡萄糖的产生，后者的作用也可通过恢复肝脏KLF15的表达而减弱。KLF15在调节致肿瘤和氨基酸降解酶的基因表达中起重要作用，二甲双胍对致肿瘤的抑制作用至少部分是通过下调KLF15和随后减弱此类基因的表达来介导的。
An increase in the rate of gluconeogenesis is largely responsible for the hyperglycemia in individuals with type 2 diabetes, with the antidiabetes action of metformin being thought to be achieved at least in part through suppression of gluconeogenesis. We investigated whether the transcription factor KLF15 has a role in the regulation of gluconeogenesis and whether KLF15 participates in the antidiabetes effect of metformin. Here we show that KLF15 regulates the expression of genes for gluconeogenic or amino acid–degrading enzymes in coordination with the transcriptional coactivator peroxisome proliferator–activated receptor γ coactivator 1α. Liver-specific ablation of KLF15 in diabetic mice resulted in downregulation of the expression of genes for gluconeogenic or amino acid catabolic enzymes and in amelioration of hyperglycemia. Exposure of cultured hepatocytes to metformin reduced the abundance of KLF15 through acceleration of its degradation and downregulation of its mRNA. Metformin suppressed the expression of genes for gluconeogenic or amino acid–degrading enzymes in cultured hepatocytes, and these effects of metformin were attenuated by restoration of KLF15 expression. Administration of metformin to mice inhibited both the expression of KLF15 and glucose production in the liver, the latter effect also being attenuated by restoration of hepatic KLF15 expression. KLF15 plays an important role in regulation of the expression of genes for gluconeogenic and amino acid–degrading enzymes and that the inhibitory effect of metformin on gluconeogenesis is mediated at least in part by downregulation of KLF15 and consequent attenuation of the expression of such genes.