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



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.



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.
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA Department of Endocrinology, School of Medicine, Pontificia Universidad Catolica De Chile, Santiago, Chile.
Rene
R
Baudrand
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Nidhi
N
Gupta
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Amanda E
AE
Garza
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Anand
A
Vaidya
Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Jane A
JA
Leopold
Cardiovascular Genetics, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT.
Paul N
PN
Hopkins
Centre d'Investigation Clinique Inserm/AP, Departement de Genetique, Hȏpital European Georges Pompidou, Paris, France.
Xavier
X
Jeunemaitre
Department MeSVA, San Salvatore Hospital, University of L'Aquila, Italy.
Claudio
C
Ferri
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Jose R
JR
Romero
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Jonathan
J
Williams
Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Joseph
J
Loscalzo
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Gail K
GK
Adler
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Gordon H
GH
Williams
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA lpojoga@partners.org.
Luminita H
LH
Pojoga
D000273:Adipose Tissue / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D051242:Caveolin 1 / Q000235:genetics*; D002784:Cholesterol / Q000378:metabolism; D050171:Dyslipidemias / Q000235:genetics / Q000378:metabolism; D000077545:Eplerenone; D005260:Female; D005787:Gene Frequency; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D008075:Lipoproteins, HDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D000074663:NADPH Oxidase 4 / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D052243:Resistin / Q000235:genetics / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism; D055815:Young Adult
D001786:Blood Glucose; C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D007328:Insulin; D008075:Lipoproteins, HDL; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; C502487:Rbp4 protein, mouse; D018161:Receptors, Mineralocorticoid; D052243:Resistin; D054839:Retinol-Binding Proteins, Plasma; C499623:Retn protein, mouse; D014280:Triglycerides; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D002784:Cholesterol; D000449:Aldehyde Reductase; D000074663:NADPH Oxidase 4; C422943:Nox4 protein, mouse; D005947:Glucose
aldosterone; caveolin 1; dyslipidemia; eplerenone; insulin resistance; mineralocorticoid receptor
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