Both the magnitude and duration of insulin signaling are important in executing its cellular functions. Insulin-induced degradation of insulin receptor substrate 1 (IRS1) represents a key negative feedback loop that restricts insulin signaling. Moreover, high concentrations of fatty acids (FAs) and glucose involved in the etiology of obesity-associated insulin resistance also contribute to the regulation of IRS1 degradation. The scavenger receptor CD36 binds many lipid ligands and its contribution to insulin resistance has been extensively studied, but the exact regulation of insulin sensitivity by CD36 is highly controversial. Herein, we found that CD36 knockdown in C2C12 myotubes accelerated insulin-stimulated Akt activation, but the activated signaling was sustained for a much shorter period of time as compared to wild type cells, leading to exacerbated insulin-induced insulin resistance. This was likely due to enhanced insulin-induced IRS1 degradation after CD36 knockdown. Overexpression of wild type CD36, but not a ubiquitination-defective CD36 mutant delayed Akt activation. We also found that CD36 functioned through ubiquitination-dependent binding to IRS1 and inhibiting its interaction with cullin 7, a key component of the multi-subunit cullin-RING E3 ubiquitin ligase complex. Moreover, dissociation of the Src family kinase Fyn from CD36 by free FAs or Fyn knockdown/inhibition accelerated insulin-induced IRS1 degradation, likely due to disrupted IRS1 interaction with CD36 and thus enhanced binding to cullin 7. In summary, we identified a CD36-dependent FA-sensing pathway that plays an important role in negative feedback regulation of insulin activation and may open up strategies for preventing or managing type 2 diabetes mellitus.Cell signaling is usually initiated by binding an activating ligand to a receptor on the plasma membrane (PM) that transmits the signal inside the cell. Distinct cellular responses and outcomes of a signaling pathway are achieved by precise regulation of its duration, magnitude and subcellular compartmentalization, which is mediated by an integrated network with multiple http://www.jbc.org/cgi

This aim of the present study was to identify the relationship between hesperidin and microRNA (miR)-132, and to study the role of hesperidin and miR-132 in the pathogenesis of non-small cell lung cancer (NSCLC). Computational analysis and luciferase assays were performed to identify the target of miR-132. Subsequently, reverse transcription-quantitative PCR and western blot assays were used to detect the effect of miR-132 and hesperidin on the expression of haematological and neurological expressed 1 (HN1) and zinc finger E-box binding homeobox 2 (ZEB2). Finally, MTT assays and flow cytometry analysis were used to investigate the effect of hesperidin on cell proliferation and apoptosis. ZEB2 was identified as a target gene of miR-132, and transfection with miR-132 mimic reduced the luciferase activity of the wild-type ZEB2 3′-untranslated region (3′-UTR) but not that of the mutant ZEB2 3′-UTR. By contrast, neither transfection with miR-132 mimic nor hesperidin treatment affected HN1 expression. Furthermore, hesperidin evidently inhibited cell proliferation and promoted apoptosis in a dose-dependent manner. Furthermore, the tumour volume in rats transplanted with NSCLC cells and treated with hesperidin was notably smaller compared with that in rats transplanted with NSCLC cells alone, while treatment with hesperidin significantly reduced the colony formation efficiency of NSCLC cells by increasing miR-132 expression and decreasing ZEB2 expression. To the best of our knowledge, the present study demonstrated for the first time that the administration of hesperidin decreased the expression of ZEB2 by upregulating the expression of miR-132, which in turn promoted apoptosis and inhibited the proliferation of NSCLC cells.

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