Plasma Levels of Retinol Binding Protein 4 Relate to Large VLDL and Small LDL Particles in Subjects with and without Type 2 Diabetes

Abstract

Background: Retinol binding protein 4 (RBP4) carries retinol in plasma, but is also considered an adipokine, as it is implicated in insulin resistance in mice. Plasma RBP4 correlates with total cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides, and may confer increased cardiovascular risk. However, controversy exists about circulating RPB4 levels in type 2 diabetes mellitus (T2DM) and obesity. Here, we analyzed the relationships of RBP4 and retinol with lipoprotein subfractions in subjects with and without T2DM. Methods: Fasting plasma RBP4 (enzyme-linked immunosorbent assay) and retinol (high performance liquid chromatography) were assayed in 41 T2DM subjects and 37 non-diabetic subjects. Lipoprotein subfractions (NMR spectroscopy) were measured in 36 T2DM subjects and 27 non-diabetic subjects. Physical interaction of RBP4 with lipoproteins was assessed by fast protein liquid chromatography (FPLC). Results: Plasma RBP4 and retinol were strongly correlated (r = 0.881, p < 0.001). RBP4, retinol and the RBP4/retinol ratio were not different between T2DM and non-diabetic subjects (all p > 0.12), and were unrelated to body mass index. Notably, RBP4 and retinol were elevated in subjects with metabolic syndrome (p < 0.05), which was attributable to an association with elevated triglycerides (p = 0.013). Large VLDL, total LDL and small LDL were increased in T2DM subjects (p = 0.035 to 0.003). Taking all subjects together, RBP4 correlated with total cholesterol, non-HDL cholesterol, LDL cholesterol, triglycerides and apolipoprotein B in univariate analysis (p < 0.001 for each). Age-, sex- and diabetes status-adjusted multivariable linear regression analysis revealed that RBP4 was independently associated with large VLDL (β = 0.444, p = 0.005) and small LDL particles (β = 0.539, p < 0.001). Its relationship with large VLDL remained after further adjustment for retinol. RBP4 did not co-elute with VLDL nor LDL particles in FPLC analyses. Conclusions: Plasma RBP4 levels are related to but do not physically interact with large VLDL and small LDL particles. Elevated RBP4 may contribute to a proatherogenic plasma lipoprotein profile.

Is the Retinol-Binding Protein 4 a Possible Risk Factor for Cardiovascular Diseases in Obesity?

“…In the Korek et al study, RBP4 levels did not correlate with BMI or fat mass and did not differ between individuals with obesity and those without obesity-RBP4 levels in both groups were 33.93 ± 4.46 and 32.53 ± 2.53 µg/mL, respectively [64]. Similar results were reported by other authors [65][66][67][68]. On the other hand, certain studies demonstrate increased RBP4 concentrations among individuals with obesity, as well as the association between RBP4 and BMI [36,69].…”

“…Moreover, in the study by Karamfilova et al, RBP4 levels ≥55 mcg/mL were associated with a 3.1 higher risk of developing metabolic syndrome [74]. Other studies also have confirmed the relationship between the components of metabolic syndrome and RBP4 levels [65,66]. Additionally, RBP4 can also be a predictor for the diagnosis of metabolic syndrome and weight regain [70,74,75].…”

“…High RPB4 levels may be involved in the pro-atherogenic plasma lipoprotein profile. In T2DM patients, RBP4 and retinol were positively correlated with triglycerides, total cholesterol, apoB, and non-HDL and low-density lipoprotein (LDL)-cholesterol [65]. Additionally, positive univariate correlations were observed with LDL-P, very-low-density lipoprotein (VLDL)-P, small LDL and HDL, and large and medium VLDL (including chylomicrons if present) [65].…”

“…In T2DM patients, RBP4 and retinol were positively correlated with triglycerides, total cholesterol, apoB, and non-HDL and low-density lipoprotein (LDL)-cholesterol [65]. Additionally, positive univariate correlations were observed with LDL-P, very-low-density lipoprotein (VLDL)-P, small LDL and HDL, and large and medium VLDL (including chylomicrons if present) [65]. According to Ingelsson et al, RBP4 levels were poorly correlated with the total cholesterol and triglycerides and were not associated with HDL-and LDL-cholesterol [37].…”

The Role of Secretory Activity Molecules of Visceral Adipocytes in Abdominal Obesity in the Development of Cardiovascular Disease: A Review

“…Upregulation of retinol-binding protein 4 (RBP4) in human blood serum is linked with insulin resistance, the development of T2DM, and such clinical manifestations of metabolic syndrome as obesity, glucose intolerance, dyslipidemia, and hypertension [111,112]. It has been demonstrated that patients with atherosclerosis of carotid arteries in combination with IHD have higher levels of RBP4 [113].…”