Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Retinol-Binding Protein 4 (RBP4)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101853

Synonyms

Historical Background

Retinol-binding protein 4 (RBP4), previously known as RBP, is a career of retinol in plasma that transport retinol from liver to peripheries. This protein mainly produced by liver and partly from adipose tissue RBP4 is encoded by the Rbp4 gene, localized in the chromosome 10q23-q24 including 8 exons. The lack of RBP4 leads to vitamin A deficiency in Rbp4 knockout mice. RBP4 that is not bound to retinol is called as Apo-RBP4, whereas retinol-bound RBP4 (holo- RBP4) associates with transthyretin (TTR) in plasma in order to stop RBP to be lost during kidney filtration. Stimulated by retinoic acid 6 (STRA6) is the cell surface receptor for RBP4. For years RBP4 was known just as a vitamin A career and a negative phase marker of acute inflammation; however, recent studies provided a novel insight to RBP4 and its role in inflammation and obesity-related complications including insulin resistance, type 2 diabetes, and cardiovascular diseases (CVD) (Wolf 2007; Kotnik et al. 2011; Zabetian-Targhi et al. 2015).

Identifying RBP4 as Marker of Insulin Resistance in Murine

The transport of glucose across plasma membranes into skeletal muscle cells and into adipocytes is facilitated by glucose transporter GLUT4. The process is stimulated by insulin. Downregulated expression of GLUT4 in state of insulin resistance in adipose tissue results in impaired glucose uptake; however, there is not the same decrease in GLUT4 expression in skeletal muscle in state of insulin resistance (Shepherd et al. 1993; Abel et al. 2001). This fact was explained by Yang et al. (2005) as they elucidated that RBP4 mRNA increases in the adipose tissue of the adipose GLUT4 knockout (adipose-Glut4−/−) mice compared with wild-type controls. RBP4 protein levels and mRNA expression is inversely correlated with GLUT4 mRNA expression in adipocytes but not in hepatocytes. GLUT4 levels correlated positively with the rate of glucose disposal. It can be concluded that there is a relation between reduced adipocyte GLUT4 and elevated RBP4 in occurrence of insulin resistance (Graham et al. 2006). Further, RBP4-overexpressing mice that express RBP4 in muscle were found to be insulin resistant, while insulin sensitivity in transgenic mice lacking RBP4 gene was greatly enhanced (Soprano and Blaner 1994). The levels of RBP4 was normalized by the antidiabetic drug rosiglitazone (Yang et al. 2005). Accordingly, it can be concluded that adipocytes may release RBP4 into the circulation as a diabetogenic signal (Wolf 2007).

RBP4 and CVD

Role of RBP4 in CVD is recently reviewed (Zabetian-Targhi et al. 2015). Elevated levels of RBP4 have been observed in different types of cardiovascular diseases (CVD). These findings mainly confirm that circulating RBP4 potentiates to be a marker of atherosclerosis.

In vitro studies showed that RBP4 has a major impact on plaque rupture by increasing proliferation of vascular smooth muscle cells (Li et al. 2015) and induces E-selectin (Farjo et al. 2012) the marker of plaque formation (De Caterina et al. 2001). RBP4 induces vascular inflammation; however, human studies found controversial results regarding the relation between RBP4 levels and CVD markers, as well as hypertension (Zabetian-Targhi et al. 2015).

The conflicting results may emerge from the various methods of RBP4 concentration measurements and differences in sample size, and demographic features. To the best of our knowledge, few longitudinal studies used accurate assays to investigate the relation between RBP4 and CVD risk factors. Longitudinal studies with larger sample sizes considering potential confounding factors are needed.

RBP4 in Relation to Inflammation and Immune Responses

RBP4 exerts its function in the pathogenesis of chronic disease through inflammation (Farjo et al. 2012; Norseen et al. 2012). Holo-RBP4 binds to STRA6 to induce insulin resistance directly in adipocytes via c-Jun N-terminal kinases pathway (Berry et al. 2011). Next, RBP4 suppresses insulin signaling through induction of suppressor of cytokine signaling 3 (SOCS3) (Deng et al. 2014). Either holo- or apo-RBP4 induces cytokine secretion in macrophages cocultured with adipocytes, so that it indirectly inhibits insulin signaling not via retinol and STRA6 but through the c-Jun N-terminal kinases pathway and Toll-like receptor 4 (Norseen et al. 2012; Deng et al. 2014). RBPs induce endothelial cell inflammation via NAD(P)H and NF-kB pathways independent of STRA6 and retinol (Farjo et al. 2012). The involvement of vitamin A in this process is unclear. Figure 1 provides a summary of these mechanisms.
Retinol-Binding Protein 4 (RBP4), Fig. 1

Role of RBP4 in inflammation. RBP4 retinol-binding protein 4, STRA6 stimulated by retinoic acid -6, SOCS3 suppressor of cytokine signaling 3, NAD(P)H Nicotinamide adenine dinucleotide phosphate, NF- κB Nuclear factor kappa

According to biological studies holo- or apo-RBP4 induces the secretion of particular inflammatory and cardiovascular risk markers in macrophages (Norseen et al. 2012) and endothelial cells (Farjo et al. 2012). Conflicting results in human studies make it hard to define the relation between cytokines and either circulating levels or adipose tissue gene expression of Rbp4.

Molecular Mechanism of Circulating RBP4 in Insulin Resistance

Insulin resistance is defined as a metabolic condition with defective insulin signaling that is found among humans and experimental animal models (Polonsky et al. 1996). It has shown that impairment of GLUT4 glucose transporter in adipose tissue results in secondary systemic insulin resistance in which adipocytes release RBP4 (Yang et al. 2005; Graham et al. 2006), suggesting that RBP4 production is tightly regulated by adipose tissue glucose uptake.

Mechanisms by which RBP4 plays its role in induction of insulin resistance is reviewed (Wolf 2007; Von Eynatten and Humpert 2008). Injection of RBP4 into wild-type mice reduces insulin-stimulated tyrosine phosphorylation of the insulin receptor substrate-1 (IRS1) in muscle. PI3K activity was reduced in muscle of mice that overexpressed RBP4. Supplementation with synthetic retinoid Fenretinide normalized RBP4 levels as well as phosphorylation level of insulin receptor substrate-1 (IRS1). Diabetogenic response of muscle to RBP4 is through reduction of glucose uptake via decrease in activation of PI3K and phosphorylation of IRS1, while liver and adipose tissue diabetogenic response to RBP4 occurs via a different mechanism. Injection of RBP4 into mice stimulated expression of the mRNA of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and increases subsequent glucose production in both mice liver and rat hepatoma cells culture without any effect on PI3K activity. In human adipocytes exogenous RBP4 reduces phosphorylation of IRS1 and downstream MAP kinases ERK1/2, and increases translocation of Glut4 with no effect on PKB phosphorylation (Öst et al. 2007). The related mechanisms are summarized in Fig. 2.
Retinol-Binding Protein 4 (RBP4), Fig. 2

Mechanisms of inducing insulin resistance by RBP4

Recently, a study found a novel mechanism involving high mobility group A1 (HMGA1) and RBP4, activating by the cAMP-signaling pathway to regulate glucose metabolism homeostasis in vivo in particular adverse metabolic conditions (Chiefari et al. 2009). HMGA1 is a small basic protein that binds to adeninethymine (A-T)-rich regions of DNA and functions mainly as a specific cofactor for gene activation (Bustin and Reeves 1996). HMGA1 indeed binds to the RBP4 locus in intact living cells and is required for proper insulin receptor gene transcription; disruption of its expression caused a type 2-like diabetic phenotype accompanied by impaired glucose tolerance coexisted with a condition of peripheral insulin hypersensitivity (Foti et al. 2005). Signal transduction pathways which raise intracellular cAMP have been reported to have a potential role in the regulation of RBP4 gene expression (Jessen and Satre 1998). HMGA1 is needed for basal and cAMP-induced retinol-binding protein 4 (RBP4) gene and protein expression in living cells of both human and mouse origin. Loss of HMGA1 expression in Hmga1-deficient mice considerably decreased RBP4 mRNA abundance and RBP4 protein production (Chiefari et al. 2009). These findings suggest a novel biochemical pathway involving HMGA1 and the RBP4.

Briefly, circulating RBP4 decreases glucose uptake via skeletal muscle and increases glucose production by liver. Increased secretion of adipose-derived RBP4 into the circulation reduces insulin-dependent glucose uptake by muscle tissue by interrupting insulin signaling in muscle cells by reducing PI3k activity and subsequent phosphorylation of the IRS-1, causing blood glucose levels to rise. In contrast, in the liver, RBP4 does not impact PI3k, but instead increases the expression of the enzyme PEPCK, which ultimately results in increased hepatic glucose output that serves to elevate blood glucose.

RBP4 as a Clinical Marker?

RBP4 was proposed as a promising biomarker in humans to link adiposity, the degree of insulin resistance, type 2 diabetes, and metabolic syndrome (Wolf 2007). Several other studies observed elevated levels of RBP4 in obesity, T2D, metabolic syndrome, and cardiovascular diseases (CVDs). However, these associations were not found by other investigations.

Although the explanations for such inconsistencies are unclear in healthy population and those with diabetes, many confounding factors such as the differences in proportion of the genetic background of the study population, consideration of renal function, as well as the methodology used to measure RBP4 levels may influence the overall conclusions, so that they make it less possible to use RBP4 as a clinical marker.

RBP4 and Lifestyle Interventions

Lifestyle interventions using low-calorie diet and exercise were applied to lower RBP4 concentrations. RBP4 levels considerably attenuated in result of low-calorie diet interventions; the effect was mostly depending on amount of weight loss along with diet quality and diversity. Dietary interventions affect RBP4 levels in only few studies independent of weight loss. The relations of RBP4 and dietary patterns, diet diversity, and food clusters need to be elucidated. (Zabetian-Targhi et al. 2015).

Summary

RBP4 have been known as a vitamin A career for years, recently implicated in chronic inflammation-related state including obesity, insulin resistance, type 2 diabetes, and cardiovascular diseases. Several mechanisms were indicated for RBP4 to induce insulin resistance in adipocytes, muscles, as well as hepatocytes. These mechanisms were evident in murine and in vitro studies, and human studies results were not inclusive according to controversies. Though, RBP4 known as a marker of CVD, inflammation, and insulin resistance with partly known mechanisms, it is not a reliable marker to use in clinical assessments due to much controversial results in human studies. These controversies were a result of differences in methodology or lack of considering potential confounder. More epidemiological studies are needed to find whether RBP4 can be used as a clinical marker or not.

References

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Menzies Institute for Medical ResearchUniversity of TasmaniaHobartAustralia
  2. 2.Department of Cellular Molecular Nutrition, School of Nutritional Sciences and DieteticsTehran University of Medical SciencesTehranIran
  3. 3.Pediatric Gastroenterology and Hepatology Research Center, Children’s Medical CenterTehran University of Medical SciencesTehranIran
  4. 4.Dietetics and Nutrition Experts Team (DiNET)Universal Scientific Education and Research Network (USERN)TehranIran