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

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.

• Authors: Rene Baudrand, Nidhi Gupta, Amanda E Garza, Anand Vaidya, Jane A Leopold, Paul N Hopkins, Xavier Jeunemaitre, Claudio Ferri, Jose R Romero, Jonathan Williams, Joseph Loscalzo, Gail K Adler, Gordon H Williams, Luminita H Pojoga
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 5 Issue 10 (09 28 2016) ISSN: 2047-9980 [Electronic] England
• PMID: 27680666 (Publication Type: Journal Article)
• Copyright: © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Chemical References

• Blood Glucose
• CAV1 protein, human
• Cav1 protein, mouse
• Caveolin 1
• Insulin
• Lipoproteins, HDL
• Mineralocorticoid Receptor Antagonists
• RNA, Messenger
• Rbp4 protein, mouse
• Receptors, Mineralocorticoid
• Resistin
• Retinol-Binding Proteins, Plasma
• Retn protein, mouse
• Triglycerides
• Spironolactone
• Aldosterone
• Eplerenone
• Cholesterol
• Aldehyde Reductase
• NADPH Oxidase 4
• Nox4 protein, mouse
• Glucose

Topics

• Adipose Tissue (metabolism)
• Adolescent
• Adult
• Aged
• Aldehyde Reductase (genetics, metabolism)
• Aldosterone (metabolism)
• Animals
• Blood Glucose (drug effects)
• Caveolin 1 (genetics)
• Cholesterol (metabolism)
• Dyslipidemias (genetics, metabolism)
• Eplerenone
• Female
• Gene Frequency
• Glucose (metabolism)
• Homeostasis
• Humans
• Hypertriglyceridemia (genetics, metabolism)
• Insulin (metabolism)
• Insulin Resistance (genetics)
• Lipid Metabolism (genetics)
• Lipoproteins, HDL (metabolism)
• Liver (metabolism)
• Male
• Mice
• Mice, Knockout
• Middle Aged
• Mineralocorticoid Receptor Antagonists (pharmacology)
• NADPH Oxidase 4 (genetics, metabolism)
• Polymorphism, Single Nucleotide
• RNA, Messenger (metabolism)
• Receptors, Mineralocorticoid (metabolism)
• Resistin (genetics, metabolism)
• Retinol-Binding Proteins, Plasma (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Spironolactone (analogs & derivatives, pharmacology)
• Triglycerides (metabolism)
• Young Adult