The global burden of metabolic syndrome (MetS) is substantial, with prevalence rates nearing 20% among adults and exhibiting a rising trend [1]. MetS is a significant precursor to diabetes, cardiovascular disease, and cancer, primarily driven by insulin resistance (IR), aging, and central obesity [[2], [3], [4], [5]]. In China, the prevalence of MetS among individuals over 40 is notably high at 33.38% [6].

Retinol, a fat-soluble vitamin, is essential for vision, immune function, and cellular protection [7]. Retinol-binding protein 4 (RBP4), primarily secreted by hepatocytes and adipocytes, acts as the main carrier for transporting retinol from the liver to extrahepatic target cells, where it exerts its physiological effects [8]. The RBP4 expression in hepatocytes plays a crucial role in mobilizing liver-stored retinol into the circulation [9]. Circulating RBP4 exists in two forms: retinol-bound and unbound. Notably, adding retinol to retinol-depleted hepatocytes has increased RBP4 secretion [9] and extracellular retinol-free apo-RBP4 may induce retinol release by adipocytes [10].

Many studies have assessed the associations between retinol and RBP4 and cardiometabolic health outcomes [8,[11], [12], [13]]. Human studies have reported both inverse [8,14,15] and positive [8,[15], [16], [17]] associations between circulating retinol and cardiovascular disease (CVD) and its risk factors. A large cohort study further revealed that retinol-associated cardiometabolic risk was lower in hypertensive participants but higher in normotensive participants [8].

Regarding RBP4, most studies, though not all, have identified positive associations with CVD, type 2 diabetes mellitus (T2DM), and obesity [8,15,[18], [19], [20]]. Additionally, Mendelian randomization analyses indicated that higher genetically predicted RBP4 levels are correlated to an increased risk of heart failure [11]. Furthermore, certain specific RBP4 variants have been linked to a heightened risk of hypertriglyceridemia [21].

Given the diverse impacts of retinol and RBP4 on MetS risk across various races and age groups, there is an urgent need for more comprehensive prospective studies to understand these relationships better.

Apolipoproteins (Apo) C1-4 are known for their dynamic exchange among lipoprotein particles such as HDL, low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) [22], with retinoids potentially upregulating ApoC1-4 levels [23,24]. A common induction of apolipoprotein genes (ApoC1, ApoC2, ApoC4) was observed in human monocytes incubated in the presence of 9-cis retinoic acid(RA), and all-trans RA [24], which is in agreement with previous results, demonstrating that retinoids increase ApoC3 expression at the transcriptional level mediated via the retinoid X receptor (RXR)-specific agonist LG1069 [23]. On the other hand, evidence suggests the C482T(ApoC3) allele as a MetS risk factor [25], supported by findings of elevated ApoC2 and ApoC3 levels in MetS patients [26], and associations of high ApoC1 and ApoC3 levels with increased triglycerides (TG) among men with MetS [27]. Additionally, ApoC4 polymorphisms have been linked to mildly elevated TG and increased coronary artery disease risk within the Chinese population [28]. The relationship between ApoCs and MetS is thought to involve disturbances in TG metabolism [25,29], IR [30,31], and inflammation [32]. However, the potential mediating role of ApoCs in the associations of blood retinol and RBP4 with MetS risk remains unexplored in prospective human studies.

The study, conducted in a middle-aged and elderly Chinese cohort, aimed to (1) examine the cross-sectional and longitudinal associations of retinol and RBP4 with MetS, as well as the potential synergistic association of retinol and RBP4; (2) investigate the relationships between retinol and RBP4 and apolipoproteins C1-4 (ApoCs), and assess how ApoCs are linked to the progression of MetS; and (3) perform path and mediation analyses to elucidate the potential roles of ApoCs in mediating relationship between retinol, RBP4, and MetS progression.