Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia. Inhibition of FoxO1-dependent expression of key autophagy genes by insulin

Translational Biology, The Hamner Institutes for Health Sciences, Durham, North Carolina 27709, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 09/2009; 284(45):31484-92. DOI: 10.1074/jbc.M109.033936
Source: PubMed


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.

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Available from: Hui-Yu Liu, Jan 16, 2016
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    • "The difference in autophagy observed in our study suggested that insulin may be a crucial regulator to autophagy under hyperglycemia conditions. Actually, high fat diet induced hyperinsulinemia was reported to suppress autophagy in mice liver [26]. However, more specific researched are needed to certificate the relationship between insulin and autophagy in skeletal muscle under hyperglycemia. "
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    • "Defective mitophagy coincides with cell models of neurological diseases including AD [31] and PD [32], as well as pancreatic β-cell dysfunction [33], cardiomyopathy [34], and hepatic IR [35]. These findings strongly implicate reduced capacity to clear defective mitochondria with complex disease. "
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    • "ER stress has been shown to activate autophagy [16], and like the UPR, autophagy may help to restore ER homeostasis [17]. In genetic and diet-induced obesity, autophagy is markedly downregulated in the liver, leading to reduced hepatic insulin action and increased ER stress, and restoration of autophagy increases insulin sensitivity [14], [18]. Mammalian target of rapamycin complex 1 (mTORC1), a central regulator of protein synthesis and cell growth, is a key inhibitor of autophagy in response to growth factors and nutrients [19] and is aberrantly hyperactivated in the obese state [20]. "
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