Small heterodimer partner (SHP) contributes to insulin resistance in cardiomyocytes.
Por:
Rodríguez-Calvo R, Chanda D, Oligschlaeger Y, Miglianico M, Coumans WA, Barroso E, Tajes M, Luiken JJ, Glatz JF, Vazquez M and Neumann D
Publicada:
1 may 2017
Ahead of Print:
16 feb 2017
Resumen:
Small heterodimer partner (SHP) is an atypical nuclear receptor expressed in heart that has been shown to inhibit the hypertrophic response. Here, we assessed the role of SHP in cardiac metabolism and inflammation. Mice fed a high-fat diet (HFD) displayed glucose intolerance accompanied by increased cardiac mRNA levels of Shp. In HL-1 cardiomyocytes, SHP overexpression inhibited both basal and insulin-stimulated glucose uptake and impaired the insulin signalling pathway (evidenced by reduced AKT and AS160 phosphorylation), similar to insulin resistant cells generated by high palmitate/high insulin treatment (HP/HI; 500µM/100nM). In addition, SHP overexpression increased Socs3 mRNA and reduced IRS-1 protein levels. SHP overexpression also induced Cd36 expression (~6.2 fold; p0.001) linking to the observed intramyocellular lipid accumulation. SHP overexpressing cells further showed altered expression of genes involved in lipid metabolism, i.e., Acaca, Acadvl or Ucp3, augmented NF-?B DNA-binding activity and induced transcripts of inflammatory genes, i.e., Il6 and Tnf mRNA (~4-fold induction, p0.01). Alterations in metabolism and inflammation found in SHP overexpressing cells were associated with changes in the mRNA levels of Ppara (79% reduction, p0.001) and Pparg (~58-fold induction, p0.001). Finally, co-immunoprecipitation studies showed that SHP overexpression strongly reduced the physical interaction between PPARa and the p65 subunit of NF-?B, suggesting that dissociation of these two proteins is one of the mechanisms by which SHP initiates the inflammatory response in cardiac cells. Overall, our results suggest that SHP upregulation upon high-fat feeding leads to lipid accumulation, insulin resistance and inflammation in cardiomyocytes.
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