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Trivalent Chromium Modulates Hexosamine Biosynthesis Pathway Transcriptional Activation of Cholesterol Synthesis and Insulin Resistance

DOI: 10.4236/ojemd.2013.34A1001    2,436 Downloads   4,374 Views   Citations

ABSTRACT

Trivalent chromium has long been recognized to benefit carbohydrate and lipid metabolism. Given emerging evidence that suggests chromium improves insulin sensitivity through the maintenance of an optimal level of plasma membrane (PM) cholesterol, we delineated the role of this micronutrient in attenuating hyperinsulinemia-induced cholesterol biosynthesis and insulin resistance. Exposing 3T3-L1 adipocytes to physiological hyperinsulinemia (500 pM 12 h), resulted in a marked impairment in insulin-stimulated glucose transport. Concurrent treatment with chromium in the picolinate form (CrPic, 10 nM 16 h) prevented against glucose transport dysfunction. Insulin signaling was neither impaired by hyperinsulinemia nor amplified by chromium to promote this protective action. Instead, it was found that hyperinsulinemia promoted an increase in PM cholesterol content that was observed to impair the acute ability of insulin to stimulate GLUT4 redistribution to the PM. Chromium prevented against the accumulation of PM cholesterol. Mechanistically, hyperinsulinemia promoted increases in O-GlcNAc modification of specificity protein 1 (Sp1), known to engage a cholesterolgenic response. Subsequent chromatin immunoprecipitation and luciferase assays revealed that hyperinsulinemia increased the binding affinity of Sp1 to the promoter region of Hmgcr, encoding 3-hydroxy 3-methyl-glutaryl-CoA reductase (HMGR), as well as HMGR promoter activity. This resulted in gains in mRNA and protein content of HMGR, with resulting elevations in PM cholesterol content. Moreover, treatment with chromium prevented this transcriptional response. Together, these data suggest a mechanism whereby CrPic affords glycemic health through inhibition of a transcriptional cholesterolgenic program detrimental to insulin action.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

B. Penque, L. Tackett and J. Elmendorf, "Trivalent Chromium Modulates Hexosamine Biosynthesis Pathway Transcriptional Activation of Cholesterol Synthesis and Insulin Resistance," Open Journal of Endocrine and Metabolic Diseases, Vol. 3 No. 4A, 2013, pp. 1-8. doi: 10.4236/ojemd.2013.34A1001.

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