Plasma retinol-binding protein 4 (RBP4) levels and risk of coronary heart disease: a prospective analysis among women in the nurses' health study.

Retinol-binding protein 4 (RBP4) is a ~21 kDa protein secreted by adipocytes and hepatocytes. Strong animal experimental data have suggested that RBP4 is causally involved in the etiology of cardiometabolic diseases.1 First, RBP4 expression is inversely regulated by Glut4 expression. Further, a PPAR-γ agonist rosiglitazone lowered adipose RBP4 expression, normalized serum RBP4 levels, and reversed insulin resistance. Lastly, transgenic overexpression of RBP4, or injection of human RBP4 in normal mice, caused insulin resistance, while genetic deletion of RBP4 or lowering circulating RBP4 levels had the opposite effects.1 Although cross-sectional human studies generated somewhat inconsistent results between RBP4 levels and insulin resistance or diabetes,1–12 recent prospective studies have shown convincing evidence that supports the findings from animal experiments.13, 14 Despite the promising evidence for insulin resistance and diabetes, data regarding RBP4 levels in relation to cardiovascular disease (CVD) are rare. Nonetheless, positive associations were documented for circulating RBP4 or RBP4 expression levels with established CVD risk factors, including metabolic syndrome,6, 7, 15 overall/central obesity,15–18 dyslipidemia,3, 5, 6, 11, 15, 18, 19 inflammatory markers,20–22 and hypertension.18, 23 Moreover, RBP4 levels have been positively associated with carotid intima-media thickness23, 24 and prevalent CVD events.15, 25, 26 An intervention study conducted among children further demonstrated that fat mass loss following lifestyle intervention resulted in reduction in RBP4 levels, which was accompanied by decreased systemic inflammation and insulin resistance.20 Similarly, in a cross-sectional study an increase in RBP4 levels over 3 years also predicted worsening of insulin resistance and cardiometabolic risk.27 However, in the only prospective study of incident coronary heart disease (CHD), RBP4 levels were not associated with CHD risk.28 Heterogeneity in study design, age, race, and other participant characteristics, and limitations of the assays used,18, 29 across previous studies may explain the discordant observations. Another caveat to be considered is that circulating RBP4 molecules exist in full-length and several truncated forms.18, 30 Although the biology of different forms of RBP4 is unknown, limited evidence suggested that some forms might be more biologically active than others.18 Since the commonly used ELISA, Western blotting, and nephelometric assays do not distinguish different forms of RBP4, few studies have examined individual forms of RBP4.18 Furthermore, depending on the affinity of antibodies to various forms of RBP4, these prevalent assays may measure different forms with different affinity,29 introducing exogenous variability in the measurement of total RBP4 levels. In the current prospective investigation, we specifically evaluated different forms of circulating RBP4 measured by a novel assay18, 31 in relation to the development of CHD among women in the Nurses’ Health Study (NHS).