Evidence That Chromium Modulates Cellular Cholesterol Homeostasis and ABCA1 Functionality Impaired by Hyperinsulinemia—Brief Report

Abstract

Objective-Trivalent chromium (Cr 3ϩ ) is an essential micronutrient. Findings since the 1950s suggest that Cr 3ϩ might benefit cholesterol homeostasis. Here we present mechanistic evidence in support of this role of Cr 3ϩ . Methods and Results-High-density lipoprotein cholesterol generation in 3T3-L1 adipocytes, which are rendered ineffective by the hyperinsulinemia that is known to accompany disorders of lipid metabolism, was corrected by Cr 3ϩ. Mechanistically, Cr 3ϩ reversed hyperinsulinemia-induced cellular cholesterol accrual and associated defects in cholesterol transporter ATP-binding cassette transporter-A1 trafficking and apolipoprotein A1-mediated cholesterol efflux. Moreover, direct activation of AMP-activated protein kinase, which is known to be activated by Cr 3ϩ , or inhibition of hexosamine biosynthesis pathway activity, which is known to be elevated by hyperinsulinemia, mimics Cr 3ϩ action. Conclusion-These findings suggest a mechanism of Cr 3ϩ action that fits with long-standing claims of its role in cholesterol homeostasis. Furthermore, these data imply a mechanistic basis for the coexistence of dyslipidemia with hyperinsulinemia.

Chromium enhances insulin responsiveness via AMPK

“…Consistent with previous observations in Cr 3+ -treated cells [2, 11–13] and tissues from Cr 3+ -supplemented animals [14–15], myotubes cultured in either control or hyperinsulinemic conditions showed a CrPic-stimulated increase in AMPK activity, as evidenced by increased phosphorylation of the catalytic alpha subunit at Threonine residue 172 (Thr172) (Fig. 4A).…”

“…1). Previous studies in 3T3-L1 adipocytes demonstrated similar increases in phosphorylation of AMPK following overnight incubations with 10 nM–1000 nM CrPic [2, 11]. Similarly, other studies have shown that long-term 24 h treatment with 10 nM CrPic increases levels of phosphorylated AMPK and ACC [12].…”

“…However, the impact of Cr 3+ supplementation on membrane cholesterol, cortical F-actin and glucose transport regulation in skeletal muscle cells is not known. Interestingly, in vitro and in vivo studies have reported that Cr 3+ treatment increases 5′-AMP activated protein kinase (AMPK) activity [2, 11–15]. Given that AMPK phosphorylates and inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGR), the rate-limiting enzyme in cholesterol synthesis, Cr 3+ could potentially mediate its beneficial effects on GLUT4 and glucose transport regulation via AMPK activation.…”

Molecular mechanisms of chromium in alleviating insulin resistance

“…Chromium has also been shown to cause an upregulation of sterol regulatory element-binding protein, a membrane-bound transcription factor responsible for controlling cellular cholesterol balance [49]. A reciprocal decrease in the cholesterol efflux protein ABCA1 has also been shown, suggesting an intricate link between chromium and cholesterol homeostasis [50, 51]. …”

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

“…Inhibition of the HBP or Sp1 binding to the DNA attenuated hyperinsulinemia-induced PM cholesterol accumulation, F-actin loss, and insulin resistance. Strikingly, these increases in cholesterol synthesis were independently found to impair cholesterol efflux processes that HBP inhibition also corrected [13].…”