eplerenone and Hypertriglyceridemia

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.

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