TITLE:
Trivalent Chromium Modulates Hexosamine Biosynthesis Pathway Transcriptional Activation of Cholesterol Synthesis and Insulin Resistance
AUTHORS:
Brent A. Penque, Lixuan Tackett, Jeffrey S. Elmendorf
KEYWORDS:
3T3-L1 Adipocytes; GLUT4; HMG-CoA Reductase; Hyperinsulinemia; Sp1
JOURNAL NAME:
Open Journal of Endocrine and Metabolic Diseases,
Vol.3 No.4A,
July
23,
2013
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.