Abstract
BackgroundMitochondrial dysfunction induces insulin resistance in myocytes via a reduction of insulin receptor substrate-1 (IRS-1) expression. However, the effect of mitochondrial dysfunction on insulin sensitivity is not understood well in hepatocytes. Although research has implicated the translational repression of target genes by endogenous non-coding microRNAs (miRNA) in the pathogenesis of various diseases, the identity and role of the miRNAs that are involved in the development of insulin resistance also remain largely unknown.MethodologyTo determine whether mitochondrial dysfunction induced by genetic or metabolic inhibition causes insulin resistance in hepatocytes, we analyzed the expression and insulin-stimulated phosphorylation of insulin signaling intermediates in SK-Hep1 hepatocytes. We used qRT-PCR to measure cellular levels of selected miRNAs that are thought to target IRS-1 3′ untranslated regions (3′UTR). Using overexpression of miR-126, we determined whether IRS-1-targeting miRNA causes insulin resistance in hepatocytes.Principal FindingsMitochondrial dysfunction resulting from genetic (mitochondrial DNA depletion) or metabolic inhibition (Rotenone or Antimycin A) induced insulin resistance in hepatocytes via a reduction in the expression of IRS-1 protein. In addition, we observed a significant up-regulation of several miRNAs presumed to target IRS-1 3′UTR in hepatocytes with mitochondrial dysfunction. Using reporter gene assay we confirmed that miR-126 directly targeted to IRS-1 3′UTR. Furthermore, the overexpression of miR-126 in hepatocytes caused a substantial reduction in IRS-1 protein expression, and a consequent impairment in insulin signaling.Conclusions/SignificanceWe demonstrated that miR-126 was actively involved in the development of insulin resistance induced by mitochondrial dysfunction. These data provide novel insights into the molecular basis of insulin resistance, and implicate miRNA in the development of metabolic disease.
Highlights
Insulin resistance is defined as the decreased responsiveness of target tissues to ordinary levels of insulin and plays a central role in the development of metabolic disorders such as type 2 diabetes, hypertension, and dyslipidemia [1,2]
These findings clearly indicate that mitochondrial dysfunction resulting from mitochondrial DNA (mtDNA) depletion induces the development of insulin resistance in hepatocytes through a reduction in the expression of insulin receptor substrate-1 (IRS-1)
We demonstrated that mitochondrial dysfunction resulting from genetic or metabolic inhibition induced the development of insulin resistance in hepatocytes via a reduction of insulin receptor substrate (IRS)-1 expression
Summary
Insulin resistance is defined as the decreased responsiveness of target tissues to ordinary levels of insulin and plays a central role in the development of metabolic disorders such as type 2 diabetes, hypertension, and dyslipidemia [1,2]. Cellular oxidative capacity, which mostly depends on mitochondrial function, is directly correlated with insulin sensitivity in skeletal muscles [5,6,7], and reduced mitochondria activity has been observed in patients with obesity and type 2 diabetes [8,9,10]. Several investigations demonstrated that skeletal muscle oxidative capacity and mitochondrial function are not a primary factor for insulin sensitivity in obese subjects [11,12,13,14], emerging evidence support that mitochondrial dysfunction may play an important role in the pathogenesis of insulin resistance and type 2 diabetes [15,16,17]. Mitochondrial dysfunction induces insulin resistance in myocytes via a reduction of insulin receptor substrate-1 (IRS-1) expression. Research has implicated the translational repression of target genes by endogenous non-coding microRNAs (miRNA) in the pathogenesis of various diseases, the identity and role of the miRNAs that are involved in the development of insulin resistance remain largely unknown
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