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. 2016 Sep 28;5(10):e003845.
doi: 10.1161/JAHA.116.003845.

Caveolin 1 Modulates Aldosterone-Mediated Pathways of Glucose and Lipid Homeostasis

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Free PMC article

Caveolin 1 Modulates Aldosterone-Mediated Pathways of Glucose and Lipid Homeostasis

Rene Baudrand et al. J Am Heart Assoc. .
Free PMC article

Abstract

Background: Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav-1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav-1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav-1-null mice and humans with a prevalent variant in the CAV1 gene.

Methods and results: In mouse studies, cav-1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high- to low-density lipoprotein (all P<0.001 versus wild type). Moreover, cav-1 knockout mice displayed hypertriglyceridemia and higher mRNA levels for resistin, retinol binding protein 4, NADPH oxidase 4, and aldose reductase in liver and/or fat tissues. MR blockade with eplerenone significantly decreased glycemia (P<0.01), total cholesterol (P<0.05), resistin (P<0.05), and described enzymes, with no effect on insulin or triglycerides. In the human study, we analyzed the CAV1 gene polymorphism rs926198 in 556 white participants; 58% were minor allele carriers and displayed higher odds of insulin resistance (odds ratio 2.26 [95% CI 1.40-3.64]) and low high-density lipoprotein (odds ratio 1.54 [95% CI 1.01-3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high-density lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cav-1 expression in adipose tissues by the rs926198 minor allele.

Conclusions: Our findings in mice and humans suggested that decreased cav-1 expression may activate the effect of aldosterone/MR signaling on several pathways of glycemia, dyslipidemia, and resistin. In contrast, hyperinsulinemia and hypertriglyceridemia are likely mediated by MR-independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype-mediated cav-1 deficiency.

Keywords: aldosterone; caveolin 1; dyslipidemia; eplerenone; insulin resistance; mineralocorticoid receptor.

Figures

Figure 1
Figure 1
A two‐week treatment with Epl in cav‐1 KO mice (gray bars) significantly decreased glucose levels (A) compared with cav‐1 KO mice (black bars) to levels observed in control wild‐type mice (white bars). The effect of Epl was not observed for insulin (B) or calculated HOMAIR (C). n=8 per group. Cav‐1 indicates caveolin 1; Epl, eplerenone; HOMA‐IR, homeostasis model assessment of insulin resistance; KO, knockout; ns, not significant.
Figure 2
Figure 2
A 2‐week treatment with Epl in cav‐1 KO mice (gray bars) significantly decreased total cholesterol levels (A) compared with cav‐1 KO mice (black bars), but levels were higher than those observed in control wild‐type mice (white bars). The effect of Epl was not significant for HDL/LDL ratio (B) or tryglicerides (C). n=6 to 8 per group. Cav‐1 indicates caveolin 1; Epl, eplerenone; HDL, high‐density lipoprotein; KO, knockout; LDL, low‐density lipoprotein; ns, not significant.
Figure 3
Figure 3
A two‐week treatment with Epl in cav‐1 KO mice (gray bars) significantly decreased plasma resistin levels (A) and resistin mRNA in liver (B) compared with cav‐1 KO mice (black bars), but levels were still higher than in control wild‐type mice (white bars). The beneficial effect of Epl was not observed for resistin mRNA in adipose tissue (C). n=6 to 8 per group. Cav‐1 indicates caveolin 1; Epl, eplerenone; KO, knockout; ns, not significant.
Figure 4
Figure 4
A two‐week treatment with Epl in cav‐1 KO mice (gray bars) significantly decreased RBP4 mRNA in liver and fat (A and B) compared with cav‐1 KO mice (black bars) to levels observed in control wild‐type mice (white bars). In addition, Epl treatment in cav‐1 KO mice (gray bars) significantly decreased NOX4 mRNA in fat (C) and aldose reductase mRNA in fat (D) compared with cav‐1 KO mice (black bars). Finally, Epl increased both G6PD activity (E) and protein expression (F, top: densitometry analysis; bottom: representative immunoblot) in cav‐1 KO mice (gray bars) compared with cav‐1 KO mice (black bars). n=4 to 8 per group. Cav‐1 indicates caveolin 1; Epl, eplerenone; G6PD, glucose‐6‐phosphate dehydrogenase; KO, knockout; NOX4, NADPH oxidase 4; ns, not significant; RBP4, retinol binding protein 4.

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