Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia INHIBITION OF FoxO1-DEPENDENT EXPRESSION OF KEY AUTOPHAGY GENES BY INSULIN
Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia INHIBITION OF FoxO1-DEPENDENT EXPRESSION OF KEY AUTOPHAGY GENES BY INSULIN
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DOI：
10.1074/jbc.m109.033936
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发表时间：
2009-11-06
影响因子：
4.8
通讯作者：
Cao, Wenhong
中科院分区：
文献类型：
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作者：
Liu, Hui-Yu;Han, Jianmin;Cao, Wenhong
自噬对于维持细胞的生存和健康至关重要。自噬通常受到氨基酸和胰岛素的抑制。目前尚不清楚在胰岛素抵抗和高胰岛素血症的情况下，自噬活性发生了什么变化。在这项研究中，我们研究了胰岛素抵抗和高胰岛素血症存在下的自噬活性及其相关机制。通过高脂肪饮食诱导小鼠胰岛素抵抗和高胰岛素血症，随后测量自噬标记物。我们的研究结果表明，自噬在胰岛素抵抗和高胰岛素血症小鼠的肝脏中受到抑制。在胰岛素抵抗和高胰岛素血症的情况下，一些关键自噬基因的转录水平也受到抑制。相反，在链脲佐菌素诱导的胰岛素缺乏小鼠的肝脏中，自噬活性增加。胰岛素缺乏小鼠肝脏中vps34、atg12和gabarappl1转录本水平升高。在有或无胰岛素的情况下，通过营养剥夺或胰高血糖素诱导培养的肝细胞自噬。胰岛素降低了vps34、atg12和gabarapl1基因的自噬活性和转录水平。胰岛素的作用在很大程度上被fox01组成核形式的过度表达所阻止。重要的是，在胰岛素抵抗的情况下，培养细胞中的线粒体自噬（mitophagy）被胰岛素抑制。总之，我们的研究结果表明，在胰岛素抵抗和高胰岛素血症的存在下，自噬活性和一些关键自噬基因的表达受到抑制。胰岛素抑制自噬涉及fox01介导的关键自噬基因转录。
Autophagy is essential for maintaining both survival and health of cells. Autophagy is normally suppressed by amino acids and insulin. It is unclear what happens to the autophagy activity in the presence of insulin resistance and hyperinsulinemia. In this study, we examined the autophagy activity in the presence of insulin resistance and hyperinsulinemia and the associated mechanism. Insulin resistance and hyperinsulinemia were induced in mice by a high fat diet, followed by measurements of autophagy markers. Our results show that autophagy was suppressed in the livers of mice with insulin resistance and hyperinsulinemia. Transcript levels of some key autophagy genes were also suppressed in the presence of insulin resistance and hyperinsulinemia. Conversely, autophagy activity was increased in the livers of mice with streptozotocin-induced insulin deficiency. Levels of vps34, atg12, and gabarapl1 transcripts were elevated in the livers of mice with insulin deficiency. To study the mechanism, autophagy was induced by nutrient deprivation or glucagon in cultured hepatocytes in the presence or absence of insulin. Autophagy activity and transcript levels of vps34, atg12, and gabarapl1 genes were reduced by insulin. The effect of insulin was largely prevented by overexpression of the constitutive nuclear form of FoxO1. Importantly, autophagy of mitochondria (mitophagy) in cultured cells was suppressed by insulin in the presence of insulin resistance. Together, our results show that autophagy activity and expression of some key autophagy genes were suppressed in the presence of insulin resistance and hyperinsulinemia. Insulin suppression of autophagy involves FoxO1-mediated transcription of key autophagy genes.