Metformin induces PGC-1a expression and selectively affects hepatic PGC-1a functions
Metformin induces PGC-1a expression and selectively affects hepatic PGC-1a functions
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DOI：
10.1111/bph.12585
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发表时间：
2014-05-01
影响因子：
7.3
通讯作者：
Hakkola, Jukka
中科院分区：
文献类型：
--
作者：
Aatsinki, Sanna-Mari;Buler, Marcin;Hakkola, Jukka
背景和目的本研究的目的是确定激活AMPK的抗糖尿病药物二甲双胍如何影响肝脏新生的主要激活因子过氧化物酶体增殖物激活物共激活物1（PGC-1）及其调节的肝功能。腺病毒过表达，siRNA和报告基因结构被用于mechanistic studies.Key ResultsMetabolism增加小鼠原代肝细胞中PGC-1 mRNA和蛋白质的表达。5-氨基咪唑-4-甲酰胺核糖核苷酸（AICAR）（另一种AMPK激活剂）具有相反的作用。二甲双胍还增加人原代肝细胞中的PGC-1;二甲双胍的这种作用被AMPK抑制剂化合物C和sirtuin 1 siRNA消除。AMPK-Ad过表达AMPK也增加PGC-1。而二甲双胍增加PGC-1，它下调致突变基因磷酸烯醇丙酮酸羧激酶（PEPCK）和葡萄糖-6-磷酸酶（G6 β）。此外，二甲双胍减弱了PGC-1过表达诱导的PEPCK和G6 β mRNA的增加，但不影响PGC-1介导的线粒体基因诱导。二甲双胍下调了PGC-1介导的Kruppel样因子15、叉头盒蛋白O 1和肝细胞NF-4等致瘤基因作用的几个关键转录因子，而上调了参与PGC-1介导的线粒体蛋白调节的核呼吸因子1。重要的是，二甲双胍选择性地影响肝脏PGC-1介导的基因调节并阻止糖异生的激活，但不影响其对线粒体基因的调节。这些结果确定了肝PGC-1功能的选择性调节是二甲双胍治疗作用中涉及的一种新机制。
Background and PurposeThe objective of this study was to determine how the AMPK activating antidiabetic drug metformin affects the major activator of hepatic gluconeogenesis, PPAR coactivator 1 (PGC-1) and liver functions regulated by PGC-1.Experimental ApproachMouse and human primary hepatocytes and mice in vivo were treated with metformin. Adenoviral overexpression, siRNA and reporter gene constructs were used for mechanistic studies.Key ResultsMetformin increased PGC-1 mRNA and protein expression in mouse primary hepatocytes. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) (another AMPK activator) had the opposite effect. Metformin also increased PGC-1 in human primary hepatocytes; this effect of metformin was abolished by AMPK inhibitor compound C and sirtuin 1 siRNA. AMPK overexpression by AMPK-Ad also increased PGC-1. Whereas metformin increased PGC-1, it down-regulated gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Furthermore, metformin attenuated the increase in PEPCK and G6Pase mRNAs induced by PGC-1 overexpression, but did not affect PGC-1-mediated induction of mitochondrial genes. Metformin down-regulated several key transcription factors that mediate the effect of PGC-1 on gluconeogenic genes including Kruppel-like factor 15, forkhead box protein O1 and hepatocyte NF 4, whereas it increased nuclear respiratory factor 1, which is involved in PGC-1-mediated regulation of mitochondrial proteins.Conclusions and ImplicationsDown-regulation of PGC-1 is not necessary for suppression of gluconeogenic genes by metformin. Importantly, metformin selectively affects hepatic PGC-1-mediated gene regulation and prevents activation of gluconeogenesis, but does not influence its regulation of mitochondrial genes. These results identify selective modulation of hepatic PGC-1 functions as a novel mechanism involved in the therapeutic action of metformin.