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

View Article: PubMed Central - PubMed

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– 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.

No MeSH data available.


Related in: MedlinePlus

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.
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jah31701-fig-0003: 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.

Mentions: We next explored the effect of MR blockade on resistin and RBP4 expression. Interestingly, eplerenone decreased circulating resistin levels and transcripts in the liver (both P<0.01) but did not reduce levels significantly in adipose tissue (Figure 3). In both adipose and liver tissues from cav‐1 KO animals treated with eplerenone, RBP4 mRNA levels dropped significantly to levels similar to those observed in WT animals (Figure 4A and 4B). In addition, AldoR and NOX4 transcript levels were significantly decreased by eplerenone treatment in cav‐1 KO adipose tissue to levels similar to those observed in WT mice (Figure 4C and 4D).


Caveolin 1 Modulates Aldosterone ‐ Mediated Pathways of Glucose and Lipid Homeostasis
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.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121487&req=5

jah31701-fig-0003: 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.
Mentions: We next explored the effect of MR blockade on resistin and RBP4 expression. Interestingly, eplerenone decreased circulating resistin levels and transcripts in the liver (both P<0.01) but did not reduce levels significantly in adipose tissue (Figure 3). In both adipose and liver tissues from cav‐1 KO animals treated with eplerenone, RBP4 mRNA levels dropped significantly to levels similar to those observed in WT animals (Figure 4A and 4B). In addition, AldoR and NOX4 transcript levels were significantly decreased by eplerenone treatment in cav‐1 KO adipose tissue to levels similar to those observed in WT mice (Figure 4C and 4D).

View Article: PubMed Central - PubMed

ABSTRACT

Background: Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav&#8208;1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav&#8208;1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav&#8208;1&ndash; mice and humans with a prevalent variant in the CAV1 gene.

Methods and results: In mouse studies, cav&#8208;1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high&#8208; to low&#8208;density lipoprotein (all P&lt;0.001 versus wild type). Moreover, cav&#8208;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&lt;0.01), total cholesterol (P&lt;0.05), resistin (P&lt;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&ndash;3.64]) and low high&#8208;density lipoprotein (odds ratio 1.54 [95% CI 1.01&ndash;3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high&#8208;density lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cav&#8208;1 expression in adipose tissues by the rs926198 minor allele.

Conclusions: Our findings in mice and humans suggested that decreased cav&#8208;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&#8208;independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype&#8208;mediated cav&#8208;1 deficiency.

No MeSH data available.


Related in: MedlinePlus