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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    • "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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    ABSTRACT: Autophagy is a conserved process in eukaryotes required for metabolism and is involved in diverse diseases. To investigate autophagy in skeletal muscle under hyperglycemia status, we established two hyperglycemia-rat models that differ in their circulating insulin levels, by glucose infusion and singe high-dose streptozotocin injection. We then detected expression of autophagy related genes with real-time PCR and western blot. We found that under hyperglycemia status induced by glucose-infusion, autophagy was inhibited in rat skeletal muscle, whereas under streptozotocin-induced hyperglycemia status autophagy was enhanced. Meanwhile, hyperglycemic gastrocnemius muscle was more prone to autophagy than soleus muscle. Furthermore, inhibition of autophagy in skeletal muscle in glucose-infusion hyperglycemia rats was mediated by the m-TOR pathway while m-TOR and FoxO3 both contributed to enhancement of autophagy in gastrocnemius muscle in streptozotocin-induced hyperglycemia rats. These data shows that insulin plays a relatively more important role than hyperglycemia in regulating autophagy in hyperglycemia rat muscle through selectively activating the m-TOR or FoxO3 pathway in a fiber-selective manner.
    PLoS ONE 02/2014; 9(2):e87254. DOI:10.1371/journal.pone.0087254 · 3.23 Impact Factor
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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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    ABSTRACT: Mitochondrial dysfunction has been implicated in the aetiology of many complex diseases, as well as the ageing process. Much of the research on mitochondrial dysfunction has focused on how mitochondrial damage may potentiate pathological phenotypes. The purpose of this review is to draw attention to the less well-studied mechanisms by which the cell adapts to mitochondrial perturbations. This involves communication of stress to the cell and successful induction of quality control responses, which include mitophagy, unfolded protein response, upregulation of antioxidant and DNA repair enzymes, morphological changes, and if all else fails apoptosis. The mitochondrion is an inherently stressful environment and we speculate that dysregulation of stress signaling or an inability to switch on these adaptations during times of mitochondrial stress may underpin mitochondrial dysfunction and hence amount to pathological states over time.
    International Journal of Cell Biology 01/2014; 2014(51):156020. DOI:10.1155/2014/156020
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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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    ABSTRACT: Obesity places major demands on the protein folding capacity of the endoplasmic reticulum (ER), resulting in ER stress, a condition that promotes hepatic insulin resistance and steatosis. Here we identify the transcription factor, Kruppel-like factor 15 (KLF15), as an essential mediator of ER stress-induced insulin resistance in the liver. Mice with a targeted deletion of KLF15 exhibit increased hepatic ER stress, inflammation, and JNK activation compared to WT mice; however, KLF15 (-/-) mice are protected against hepatic insulin resistance and fatty liver under high-fat feeding conditions and in response to pharmacological induction of ER stress. The mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cellular energy homeostasis, has been shown to cooperate with ER stress signaling pathways to promote hepatic insulin resistance and lipid accumulation. We find that the uncoupling of ER stress and insulin resistance in KLF15 (-/-) liver is associated with the maintenance of a low energy state characterized by decreased mTORC1 activity, increased AMPK phosphorylation and PGC-1α expression and activation of autophagy, an intracellular degradation process that enhances hepatic insulin sensitivity. Furthermore, in primary hepatocytes, KLF15 deficiency markedly inhibits activation of mTORC1 by amino acids and insulin, suggesting a mechanism by which KLF15 controls mTORC1-mediated insulin resistance. This study establishes KLF15 as an important molecular link between ER stress and insulin action.
    PLoS ONE 10/2013; 8(10):e77851. DOI:10.1371/journal.pone.0077851 · 3.23 Impact Factor
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