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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 95-107

The associations between retinol binding protein-4 and cardiometabolic profile: Intertwined-intricate relationship


Department of Pharmacology, Toxicology and Medicine, College of Medicine Almustansiriya University, Baghdad, Iraq

Date of Submission28-Jan-2020
Date of Acceptance25-Feb-2020
Date of Web Publication17-Jun-2020

Correspondence Address:
Prof. Hayder Mutter Al-Kuraishy
Department of Pharmacology, Toxicology and Medicine, College of Medicine Almustansiriya University, P.O. Box 14132, Baghdad
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_6_20

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  Abstract 


Retinol binding protein-4 (RBP4) is a new adipokine synthesized by the liver and adipose tissue, and its secretion depends on retinol concentrations and reflects visceral fat mass. RBP4 serum levels are regarded as a new biomarker in follow-up and diagnosis of overweight and obesity and other cardiometabolic disorders, such as hypertension, ischemic stroke, and dyslipidemia. Different drugs such as statins, fibrates, glucagon-like peptide 1 (GLP-1), dipeptidyl peptidase-IV (DPPIV) inhibitors, and thiazolidinediones (TZDs) have been reported to reduce RBP4 levels. The objectives of the present study were to illustrate the role of RBP4 in different cardiometabolic disorders and to explore the conflicting about the effect of different drug groups on the circulating RBP4 levels. A multiplicity of search strategies took on and assumed which included electronic database searches of Scopus, Web of Science, Medline, Cochrane Central Register of Controlled Trials, and PubMed using MeSH terms, keywords, and title words during the search. RBP4 plasma levels are mainly correlated with visceral adiposity and less to the subcutaneous adipose tissue. Statins may reduce or increase RBP4 plasma levels. Fibrate drugs, TZDs, DPPIV inhibitors, and GLP-1 agonists reduce RBP4 plasma levels through suppression of adipose tissue RBP4 mRNA and elevation of adiponectin levels. Metformin reduces circulating RBP4 levels through the improvement of insulin sensitivity, upregulation of glucose transporter 4 (GLUT4), and activation of adipocytes PPARα.

Keywords: Cardiometabolic disorders, fibrate drugs, insulin sensitivity, retinol binding protein-4, statins


How to cite this article:
Naji MT, Sami OM, Shams HA, Abdul-Hadi MH, Al-Kuraishy HM, Al-Gareeb AI, Al-Harchan NA. The associations between retinol binding protein-4 and cardiometabolic profile: Intertwined-intricate relationship. Biomed Biotechnol Res J 2020;4:95-107

How to cite this URL:
Naji MT, Sami OM, Shams HA, Abdul-Hadi MH, Al-Kuraishy HM, Al-Gareeb AI, Al-Harchan NA. The associations between retinol binding protein-4 and cardiometabolic profile: Intertwined-intricate relationship. Biomed Biotechnol Res J [serial online] 2020 [cited 2020 Nov 28];4:95-107. Available from: https://www.bmbtrj.org/text.asp?2020/4/2/95/286849




  Introduction Top


Retinol binding protein-4 (RBP4) is a new adipokine of 21-kDa protein binds retinol, which was discovered in 2005 by a researcher at Harvard University. RBP4 is synthesized by the liver and adipose tissue, and its secretion depends on retinol concentrations and reflects visceral fat mass. The synthesis of RBP4 may occur in the endometrial and extra-embryonic tissues in some animal species. The main function of RBP4 is binding of the circulating retinol (Vitamin A) and forms a soluble complex, protects it from oxidation, and reduces the toxic effect of retinol.[1]

There are three main types of RBP4 which are (1) plasma RBP4 that transports retinol from the liver to the peripheral tissues, (2) cellular RBP4 (CRBP4) that increases the storage of retinol and its metabolites in a form of retinoic acid or retinyl-ester, and (3) cellular retinoic acid binding protein (CRABP) that regulates the availability retinoic acid to the nuclear receptors.[2] Moreover, the surface receptor of retinoic acid 6 mediates the uptake of retinoic acid from RBP4. Further, intracellular retinoid concentration is regulated by CRBP receptors and cytoplasmic retinoic acid RBP (CRABPs) receptors. There are four types of CRBP receptors, which are CRBP1, CRBP2, CRBP3, and CRBP4, compared with two isoforms of CRABP which are CRABP1 and CRABP2. Specifically, CRBPs bind retinol, while CRABPs bind retinoic acid. Besides, retinoids activate specific nuclear receptors, which are retinoic acid receptors and retinoid X-receptors (RXRs) [Figure 1].[3]
Figure 1: Retinol binding protein-4 and retinol effect

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Visceral adipose tissue is regarded as a second important source of RBP4, as the level of RBP4 is correlated with body mass index (BMI) and adipose tissues.[4] Moreover, RBP4 is regarded as a pro-inflammatory mediator that contributes to different metabolic disorders, such as insulin resistance, type 2 diabetes mellitus (T2DM), stroke, and other cardiometabolic disturbances.[5] Therefore, the objectives of this study were to elucidate and review the metabolic effect of RBP4 regarding the therapeutic modalities in different metabolic disorders.


  Literature Search Strategy Top


In general, an endeavor of this study article was to present a mini-review regarding the potential metabolic effect of RBP4. Evidence from experimental, preclinical, and clinical studies is evaluated, given the nature of the subject area; it remains clear that this literature search cannot be regarded as a systemic review.

A multiplicity of search strategies took on and assumed that included electronic database searches of Scopus, Web of Science, Medline, Cochrane Central Register of Controlled Trials, and PubMed using MeSH terms, keywords, and title words during the search. The terms used for these searches were as follows: [RBP4] AND [obesity OR dyslipidemia OR cardio-metabolic]. [RBP4 OR vitamin binding protein OR retinoic acid] AND [stoke OR hypertension, heart failure, obesity, insulin resistance, insulin sensitivity]. [RBP4 OR vitamin binding protein OR retinoic acid] AND [statins OR fenofibrate OR orphan drugs OR metformin OR glucagon-like peptide 1 (GLP-1) OR dipeptidyl peptidase-IV inhibitors (DPPIV) OR thiazolidinediones (TZDs)]. Reference lists of identified and notorious articles were reviewed. In addition, only English articles were measured and case reports were not concerned in this review. The key features of recognized appropriate search studies were considered and the conclusions are summarized in a mini-review.


  Retinol Binding Protein-4 and Obesity Top


RBP4 is highly expressed circulating adipokine linked with high BMI and obesity since high RBP4 serum levels are associated with adiposity and related metabolic disturbances.[6] Therefore, RBP4 serum levels are increased in obese subjects which increase the morbidity in those subjects compared to lean subjects.[7] RBP4 in obese subjects is mainly linked to abdominal obesity since it positively correlated with BMI, waist circumference, and waist–hip ratio.[8] Similarly, RBP4 serum levels are more correlated with the visceral compared to subcutaneous adipose tissues. Hence, the reduction of visceral but not subcutaneous adipose tissue mass by weight loss may reduce RBP4 levels significantly. The reason beyond this condition is the overexpression of RBP4 mRNA in the visceral compared to the subcutaneous adipose tissues.[9] On the other hand, RBP4 plasma levels are correlated with liver fat, nonalcoholic fatty liver diseases, and ectopic fat deposition in the muscles.[10] In obese subjects, different adipocytokines such as adiponectin and leptin are elevated, with a different association to RBP4 plasma levels, which might be positive, negative, or no association.[11],[12] Therefore, the association of RBP4 level and adipocytokines is complicated as leptin therapy may increase or decrease the expression of visceral RBP4 mRNA.[13] As a result, high levels of RBP4 in obesity might be either due to the expanded adipose tissue or due to the association with other adipokines. Moreover, RBP4 plasma levels reflect body energy balance as it decreases following weight loss and a low calorie diet.[14] Similarly, intensive but not low–moderate exercise reduces RBP4 plasma levels due to the improvement of skeletal muscle insulin sensitivity.[15] Shirai et al. found that RBP4 and retinol metabolism in the peripheral tissues are affected by high-fat-diet-induced obesity and insulin resistance in rats.[16] As well, RBP4 is linked to the obesity-induced comorbidities, through induction of inflammatory reactions and insulin resistance even in young obese subjects. Thus, RBP4 serum levels are regarded as a new biomarker in follow-up and diagnosis of overweight and obesity.[17]


  Retinol Binding Protein-4 in Insulin Resistance and Diabetes Mellitus Top


High visceral adipose tissue is linked with the development of insulin resistance (IR) and T2DM. Therefore, the reduction of visceral fat mass by surgical omentectomy will improve insulin sensitivity and reduces IR in obese subjects.[18] RBP4 from visceral adipocytes downregulates glucose transporter 4 (GLUT4) in the adipose tissue, liver, and muscles and contributes to the development of IR and T2DM. GLUT4-knockout mice develop systemic IR with an elevation of RBP4 serum levels. Besides, the administration of fenretinide, a synthetic retinoid, decreases IR and improves insulin sensitivity through the suppression of RBP4.[19] It has been shown that RBP4 serum levels are increased in subjects with impaired glucose tolerance and lean normoglycemic individuals with a positive family history of T2DM. Thus, RBP4 serum levels are positively correlated with IR and BMI and negatively correlated with high-density lipoprotein (HDL) and insulin sensitivity in obese subjects. Likewise, circulating RBP4 serum levels are positively correlated with fasting blood glucose and glycated hemoglobin and negatively correlated with glucose disposal rate, insulin sensitivity, β-cell function, and hepatic glucose production.[20]

The link between high RBP4 serum levels and IR has been elucidated in different studies that illustrated an association between single-nucleotide polymorphisms (SNP) in the genes of IR and RBP4. Munkhtulga et al. found that SNP of T2DM is located in the promoter region of RBP4 that enhances the transcription of RBP4 gene, causing an increase in the RBP4 serum levels in patients with T2DM.[21] Janke et al. did not find any associations between RBP4 mRNA in adipose tissue and IR.[22] Therefore, RBP4 serum level in patients with obesity and/or T2DM is correlated to RBP4 mRNA in the visceral and subcutaneous adipose tissue, although it is more in visceral one. Besides, the high RBP4 serum level in patients with IR leads to high portal RBP4 levels and subsequent hepatic IR.[23] On the other hand, IR may elevate RBP4 through theinduction of inflammatory changes in the peripheral and adipose tissues. Adipose tissue macrophages may produce RBP4 causing IR with a closed vicious cycle. In addition high RBP4 level is correlated with low-grade inflammation and macrophage infiltration in the adipose tissue since the circulating level of RBP4 is linked to a marker of macrophage overactivity. Indeed, RBP4 activates pro-inflammatory cytokine secretion from mouse macrophages such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, IL-2, and IL-12 through JAK2/STAT5 signaling pathway. More to the point, RBP4 inhibits the expression of PPAR, which is important for insulin signaling and negative regulation of inflammations.[24],[25] Hence, RBP4 leads to IR directly or indirectly through the activation of inflammatory pathways. More specifically, plasma RBP4 is found in two forms, holo-RBP4 (bound to retinol) and apo-RBP4 (free one). Apo-RBP4 is more potent about 10–100 folds than holo-RBP4 in the induction of the release of pro-inflammatory cytokine secretion from macrophage. IR is more related to high apo-RBP4 than total RBP4 serum levels, suggesting retinol-independent effect of RBP4 in the induction of IR.[26] Consequently, RBP4, mainly apo-RBP4, is regarded as a novel biomarker in the screening of visceral adiposity, IR, and risk of T2DM in genetically susceptible subjects.

RBP4 leads to IR through different pathways, which are the inhibition of muscle insulin-stimulated phosphoinosititide-3-kinase activity and tyrosine phosphorylation, stimulation of hepatic gluconeogenic enzyme phosphoenolpyruvate kinase, protein kinase phosphorylation, suppression of mitogen-activated protein kinase (MAPK)-ERK1/2 pathway, and downregulation of GLUT4.[27]

Therefore, impaired GLUT4 at the visceral adipose tissue leads to the release of RBP4 from affected adipocytes causing impairment of muscle glucose uptake and induction of hepatic glucose release that together causes IR and hyperglycemia. For that reason, RBP4 is regarded as a diabetogenic factor that links obesity, IR, and T2DM.[28]

It is inspiring to cognize that high plasma level RBP4 might be a consequence of hyperinsulinemia. However, patients with T2DM have lower fasting insulin than patients with impaired glucose tolerance with the same degree of IR and similar levels of RBP4. Thus, the reduction of insulin level does not decide RBP4 plasma level, as RBP4 is reduced in patients with T1DM and returned to normal following insulin therapy.[29] Because RBP4 is the main transporter protein of retinol (Vitamin A), possibility of involvement of this vitamin in the pathogenesis of IR and T2DM may raise, although synthetic retinoid improves IR through the reduction of RBP4. Thus, it will be noteworthy to conclude whether dietary retinol influences insulin sensitivity in human T2DM or not?[30]


  Retinol Binding Protein-4 and Dyslipidemia Top


Hypertriglyceridemia is a common lipid abnormality, especially in T2DM and IR, as the reduction of insulin activity is associated with a reduction in the lipoprotein lipase activity and an increase in the hepatic triglyceride production. However, experimental administration of RBP4 in mice stimulates hepatic triglyceride production and very low-density lipoprotein (VLDL) secretion.[31] Therefore, RBP4-induced hypertriglyceridemia directly or indirectly may induce IR and/or T2DM. Furthermore, RBP4 activates transcription and secretion of cellular apolipoprotein B (ApoB). Both intracellular ApoB and microsomal triglyceride transfer protein (MTP) transfer lipids to ApoB. High RBP4 activates MTP for triglyceride synthesis and release, with regression of LDL receptors through activation of preprotein converts subtilins kinase-9 expression.[32] Plasma levels of RBP4 relate to the serum lipid profile as circulating RBP4 is negatively correlated with HDL but positively correlated with LDL-cholesterol, total cholesterol, triglyceride, ApoB, and small-dense LDL (sdLDL).[33] RBP4 is regarded as a predictor of diet-induced ApoB and sdLDL changes due to the similarity in the lipoprotein between RBP4 and ApoB-containing lipoprotein. Further, RBP4 affects the metabolic pathways that are responsible for ApoB-containing lipoprotein metabolism.[34] As well, RBP4 increases LDL and VLDL due to the stimulation of hepatic lipase activity and secretion of triglyceride-rich ApoB lipoprotein, causing hypertriglyceridemia.[35] Hence, RBP4 may elevate serum triglyceride levels of hepatic and extrahepatic pathways.

In this context, RBP4 has an important role in the modulation of lipid metabolism and homeostasis through regulating the expression of different genes involved in intestinal and hepatic triglyceride and VLDL productions and secretions. Similarly, RBP4 reduces β-oxidation and catabolism of VLDL via regulating and modulating the expression of APO C-III (which delays VLDL catabolism).[36] On the other hand, RBP4 does not directly affect the LDL production or its particle size; however, there is an independent association between RBP4 and synthetic LDL (sLDL) and development of atherosclerosis and cardiometabolic complications.[37] RBP4-induced IR leads to an increase in the free fatty acid concentrations and flux to the liver that encourage VLDL production. Hence, high VLDL will promote the formations of LDL, sLDL, and HDL through hepatic cholesterol ester transfer protein.[38] As well, elevated RBP4 alone or with other inflammatory changes induces dysfunctional HDL through a change in cholesterol composition and size of HDL, induces changes in cholesterol receptors, and inhibits the secretion of hepatic cholesterol. This abnormal HDL contributes to the formation of sLDL, with subsequent endothelial dysfunction and cardiovascular complications.[39] In this regard, the reduction of RBP4 serum levels by fenretinide will improve HDL-cholesterol levels.[40]

Come to the point, RBP4 plays a potential role in the pathogenesis of dyslipidemia through promoting the synthesis of VLDL, oxidized LDL (oxLDL), sLDL, and triglyceride with the induction of dysfunctional HDL, which together participated in the development and progression of atherosclerotic changes and cardiovascular complications.


  Retinol Binding Protein-4 and Cardiovascular Disorders Top


It has been speculated that RBP4 is implicated in the cardiometabilc complications through induction and initiation of inflammatory and immunological changes in the vascular and adipose tissues.[41] High circulating RBP4 levels are linked to the development and progression of different cardiovascular disorders, including cardiomyopathy, coronary artery disease (CAD), heart failure (HF), carotid stenosis, and atherosclerosis.[42],[43] However, Mahmoudi et al. observed an insignificant correlation of RBP4 levels with cardiometabolic disorders mainly in patients with CAD and T2DM.[44] Nevertheless, RBP4 plasma levels are associated with the development of endothelial dysfunction and clinical atherosclerosis through the induction of vascular inflammation and endothelial oxidative stress.[45] RBP4 provokes endothelial inflammations by increasing the secretion of pro-inflammatory mediators, such as endothelial leukocyte adhesion molecule 1 (E-selectin), vascular cell adhesion molecule 1, intercellular adhesion molecule 1, monocyte chemoattractant protein (MCP-1) and IL-6 from endothelial cell, which recruits activated leukocytes to the vascular endothelium.[46] As well, Farjo et al. confirmed that apo-RBP4 is potent as holo-RBP4 in the induction of endothelial dysfunction and inflammation via activation of NF-kB and NADPH oxidase.[47] More to this point, RBP4-induced oxidative stress also leads to endothelial inflammation and dysfunction via induction of lipid peroxidation. It has been reported that RBP4 plasma levels are positively correlated with biomarkers of oxidative stress, such as malondialdehyde and 8-isoprostane.[48] Therefore, RBP4 leads to endothelial and vascular dysfunction with the development of atherosclerotic alterations via induction of endothelial inflammatory and oxidative stress changes.

Different studies illustrated that RBP4 level is involved in plaque formation, enlargement, and rupture; thus, RBP4 levels reflect plaque severity in patients with clinical atherosclerosis. These findings might explain the positive correlation between high circulating RBP4 level and carotid intima-media thickness as an indicator of subclinical atherosclerosis.[49],[50] In addition, Silverstein showed that macrophage-derived RBP4 might play an important role and acts as an autocrine factor in the formation of foam cells at the atherogenic environment via activating the production of inflammatory mediators such as oxLDL and prostanoids. These mediators activate PPAR-γ and liver X-receptors to create a loop with the CD36 promoter for the stimulation of endothelial lipid uptake and foam cell formation.[51] These pathological changes reduce endothelial functions and activated vasodilatation; thus, RBP4 levels are inversely correlated with flow-mediated vasodilatation in patients with T2DM.[43] As a result, RBP4 is regarded as a predictive factor for cardiovascular disorders and complications in patients with dyslipidemia. In addition, it predicts the severity of CAD independent of BMI and visceral adiposity.[11] It is also interesting to observe that a controversial study reported nonlinear relationship between high circulating RBP4 levels and risk of cardiovascular complication, which might due to different factors such as gender, age, and ethnicity, which might affect the metabolic response for high circulating RBP4 levels.[52] In addition to this, compensatory hyperinsulinemia due to RBP4-induced IR leads to the induction of vascular smooth muscle cell proliferation and subsequent atherosclerosis.[53] It has been taken into account by a prospective study involving 1000 patients with CAD found that RBP4-circulating levels are positively correlated with a risk score of CAD. Nonetheless, after adjustment for the risk factors, this positive correlation disappears, suggesting that RBP4 was not a good predictive factor for CAD.[54]

To the best of our knowledge, the relationship between RBP4-circulating levels and cardiovascular risk score is not well related, so this relationship is still contentious despite various studies.

Large epidemiological and longitudinal studies illustrated that RBP4 is linked with the development of hypertension, myocardial infarction, and endothelial dysfunction independent of metabolic syndrome (MetS). Plaque echogenecity, atherosclerosis, and intima-media thickness are important consequences of high circulating RBP4, which causes vasoconstriction and hypertension.[55],[56]

Retinol binding protein-4 in hypertension

It has been noticed that RBP4 may be a proxy biomarker of intima-media thickness and impairment of vascular reactivity for the development of systolic hypertension. In spite of this, the relationship between hypertension and RBP4 plasma levels is uncertain. RBP4-induced hypertension may be mediated by a different pathway from hereditary, environmental, and IR pathway.[57] IR induced by RBP4 leads to the activation of rennin-angiotensin system, sodium retention, microvascular remodeling, and endothelial dysfunction, which collectively lead to hypertension.[58]

RBP4 also increases systolic blood pressure through modulation of RXR and PPAR, which mutually impair vascular reactivity and cause vasoconstriction and hypertension.[59] Michel and Vanhoutte showed that RBP4 leads to vasoconstriction and impairs flow-mediated vasodilatation through suppression of endothelial nitric oxide synthase (eNOS).[60] In addition, Solini et al. confirmed that RBP4 as an important adipocytokine is linked to the development of hypertension in women.[61] However, Stepan et al. illustrated insignificant correlation between RBP4 plasma levels and markers of preeclampsia, suggesting that RBP4 did not play any role in the pathogenesis of preeclampsia.[62] More to this point, RBP4 plasma level is closely related to hypertension in prehypertensive Chinese.[63] Nevertheless, a multiple regression that is done by Chiba et al. revealed that RBP4 plasma levels are significantly correlated with systolic blood pressure independently of cardiometabolic and anthropometric profiles.[64] Therefore, these studies confirm the association between hypertension and RBP4 plasma levels, regardless of associated comorbidity factors.

Retinol binding protein-4 in coronary artery disease

Sun et al. found that CAD is connected with higher epicardial RBP4 and lower GLUT4 concentrations in the subcutaneous and epicardial adipose tissue. In addition, full-length RBP4 but not the truncated one is linked with a three-fold increased risk of CAD.[65] High circulating RBP4 provokes coronary endothelial dysfunction, atherosclerotic changes, and pro-inflammatory changes. Besides, it causes hypertension and dyslipidemia, which are regarded as the risk factors for CAD.[66] Hence, high RBP4 is positively correlated with cardiovascular risk factors of CAD. A longitudinal study done by Mallat et al. observed that RBP4 plasma levels are only associated with CAD in the first 8 years of follow-up, after that this association is attenuated.[67] There are different aspects and controversies about the association between RBP4 plasma levels and CAD. von Eynatten et al. illustrated a poor role of RBP4 plasma level in predicting the severity of CAD despite the important association with lipid metabolism.[68] However, Lambadiari et al. confirmed the connection between RBP4 plasma levels and CAD severity but not with acute myocardial infarction.[69] The association between high RBP4 plasma level and CAD is related to coronary endothelial inflammation, induction of pro-inflammatory molecules, and activation of coronary endothelial NADPH oxidase, TNF-α, and NF-kB pathway that is caused by elevated RBP4 plasma level.[70] As well, high circulating RBP4 activates the production of pro-atherogenic lipoproteins, through structural and functional changes of protective HDL.[66] On the other hand, Wang et al. found that RBP4 plasma levels are positively associated with total testosterone and reduced in patients with CAD, highlighting the protective role of RBP4 against the development of CAD.[71] Despite these scientific backgrounds that link the potential role of RBP4 with the risk factors and incidence of CAD, the relationship and the association between RBP4 and CAD remain unknown and depend on the scientific expectations. Likewise, different previous studies ignore these associations and explain it depending on the methodological approach and analysis of RBP4 in respect to the metabolic risk factor, in addition to CAD and other ischemic heart diseases. Besides, the discrepancies among various clinical studies might relate to the heterogeneity in the study design, participant characteristics, age, gender, and race.[72] However, a recent study by Sun et al. confirmed that high RBP4 is linked with the presence and severity of CAD.[73]

Therefore, till now, the link between RBP4 and CAD is not confirmed and explained precisely; hence, long-term prospective studies are recommended to proof this relation with regarding and/or excluding other cardiometabolic risk factors which might affect RBP4 plasma levels.

Retinol binding protein-4 in heart failure

It has been shown that chronic HF is associated with IR, hyperinsulinemia, impaired glucose tolerance, and development of overt T2DM. In addition, the alteration of glucose metabolism due to IR and T2DM leads to progressive deterioration of myocardial function via activation of oxidative stress and then development of HF.[74] It is well known that the diabetogenic effect of RBP4 may contribute to the development of HF through induction of IR. As well, the pathological and compensatory responses during HF also participate in the expansion of IR via metabolic derangements. However, high circulating RBP4 plasma levels have been reported in the inflammatory dilated cardiomyopathy.[75] Moreover, RBP4 plasma levels and glucose indices are elevated in HF and subsequently reduced following the mechanical and pharmacological interventions for HF in nondiabetic subjects. Proper management of HF also reduces fasting glucose and pro-inflammatory mediators; herein, the reduction in the plasma levels of RBP4 following the treatment of HF reflects adequate circulation and reduction of systemic inflammations.[76] Chronic HF leads to hemodynamic failure and tissue ischemia/hypoxia that provokes the generation of free radicals, which per se activate the expression of RBP4 gene. Increasing RBP4 plasma levels in HF act as protective factor as it causes peripheral vasodilatations through the activation of eNOS/Akt pathway.[77] Nevertheless, the reduction of RBP4 plasma levels following management and unloading of HF might be due to the improvement of peripheral perfusion and neurohormonal signals. However, RBP4 plasma levels may be regarded as a novel biomarker screening the outcomes of patients with HF.

Retinol binding protein-4 links insulin resistance and heart failure

Chronic inflammation plays an important role in the development of HF and IR. Interestingly, Toll-like receptor 4 (TLR4), which is the chief modulator of innate immunity and cytokine activation, plays an important role in the impairments of insulin signaling and cardiac inflammation.[78] In HF, there is a progressive high expression of TLR4, and so, TLR4 antagonists attenuate cardiac hypertrophy and development of HF in mice.[79] RBP4 stimulates TLR4 leading to IR, HF, and other cardiovascular complications, so it is regarded as potential biomarker that links IR with HF. It has been shown that RBP4 activates cardiac TLR4 receptor via complex pathways, including CD14 and myeloid differentiated protein-2.[80] Therefore, IR and HF form a vicious cycle that regards high mortalities in patients with HF and T2DM, through activation of RBP4 [Figure 2].[81] Kraus et al. found that RBP4 through TLR4 produces a direct effect on the cardiomyocytes via increasing cell size and protein synthesis, causing cardiac hypertrophy, or indirectly via induction of systemic and cardiac IR.[82] Therefore, at the heart of the dilemma, the pharmacological inhibition of TLR4 receptor attenuates cardiac hypertrophy and interrupts the vicious cycle between IR and HF.[83] Besides, RBP4 activates specific inflammasome called nucleotide-binding oligomerization domain-like receptor pyrin 3 which is implicated and linked with the development of HF.[84] Similarly, RBP4 activates the generation of free radicals within cardiomyoctes and consumes the endogenous antioxidant capacity; thus, treatment with antioxidants may prevent RBP4-induced cardiac oxidative stress and cardiomyocytes injury.[85] On the other hand, in HF, rennin-angiotensin system is overactivated, so high angiotensin II (Ang II) level leads to the induction of IR through activation of inflammation, lipogenesis, and reactive species formations in the adipocytes.[86] As well, Ang II provokes adipocyte RBP4 formation and secretion. Therefore, Ang II antagonist inhibits adipocyte RBP4 so prevents RBP4-induced HF in patients with visceral adipocity.[87]
Figure 2: Retinol binding protein-4 links insulin resistance and heart failure

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Retinol binding protein-4 in ischemic stroke

Stroke is defined as a focal neurological deficit and represents the most common neurological disorder. 85% of stroke caused by ischemia (ischemic stroke) and 15% by hemorrhage (hemorrhagic stroke).[88] RBP4 delivers retinol from the liver to the peripheral tissues and brain, which is important for brain development via neurogenesis and neuroplasticity. In addition, RBP4 and retinol regulate neuroinflammations during ischemic stroke.[89] Sasaki et al. found that high circulating RBP4 levels are associated with ischemic stroke and regarded as a risk factor for the development of ischemic stroke. Indeed, RBP4 levels are more correlated with ischemic stroke than hemorrhagic stroke and could be used as a biomarker in the differentiation between stroke types.[90] Furthermore, a recent study by Zhu et al. illustrates that high circulating RBP4 levels in patients with ischemic stroke reflect underlying involvement of insulin signaling and Vitamin A metabolism as causative factors for ischemic stroke. In addition, RBP4 is regarded as a prognostic factor for ischemic stroke as it predicts poor functional outcomes compared to the other cardiometabolic factors.[91] In contrast, Rist et al. confirmed that high circulating RBP4 levels do not increase the risk of ischemic stroke.[92] Interestingly, the link between high circulating RBP4 and ischemic stroke is through RBP4-induced oxidative stress/inflammatory pathway which is augmented during cerebral ischemia via activation of TLR4/JNK/p38 and MAPK signaling.[93] In addition, endothelial dysfunction and subclinical atherosclerosis that are induced by high levels of RBP4 might contribute to the induction of ischemic stroke. What's more, high RBP4 level increases systemic blood pressure before and during the acute phase of ischemic stroke.[91] To our knowledge and to date, high RBP4 level provokes cardiometabolic risk factors such as dyslipidemia, IR, hypertension, atherosclerosis, and endothelial dysfunction, which are important in the development of stroke.[94]


  Retinol Binding Protein-4 in Metabolic Syndrome Top


MetS is a group of metabolic disorders, including central obesity, hyperglycemia, dyslipidemia, and hypertension. MetS is commonly associated with cardiovascular disorders and T2DM.[95] Animal model study observes that RBP4 induces IR and other components of MetS in mice through activation of hepatic phosphenolpyruvate kinase and downregulation of muscle GLUT4.[96] Clinical and experimental study by von Eynatten and Humpert illustrated that high circulating RBP4 levels are associated with the severity of hypertension, IR, adiposity, and other arms of MetS. This association is independent of geographical and anthropometric factors, as well as lifestyle and family history.[97] High circulating RBP4 in MetS might be due to low adiponectin and high inflammatory biomarkers in patients with obesity and IR, which are the main components of MetS. However, the association between RBP4 and C-reactive protein (CRP) and adiponectin has not been evaluated precisely in large-population study.[48] It has been noticed that high RBP4 and CRP with low adiponectin serum levels are intimately linked with the development of MetS. Nevertheless, independent high circulating RBP4 may lead to MetS despite low CRP and high adiponectin serum levels, suggesting a novel pathway of RBP4-induced MetS.[98] Moreover, atherogenic dyslipidemia induced by RBP4 increases the risk of cardiovascular complications in patients with MetS. However, it is still unclear that high RBP4 might cause dyslipidemia or vice versa. In addition, nuclear X-receptors which are activated by retinol play an important role in lipid homeostasis, suggesting that RBP4/retinol could induce MetS via the induction of dyslipidemia.[99] Engagingly, IR, hyperinsulinemia, and dyslipidemia may provoke RBP4 synthesis in ectopic fat and liver since high circulating RBP4 is closely associated and correlated with the mass of liver fat.[100] Alternatively, visceral obesity tends to be the most obvious feature of MetS, it is associated with high RBP4 serum level, but high circulating RBP4 levels in patients with MetS may not be a purely an outcome of visceral adiposity as RBP4 levels might be similar in obese and healthy subjects.[101]

Aeberli et al. illustrated that RBP4 serum levels are correlated with MetS in the pubertal and prepubertal period. Therefore, RBP4 links childhood obesity with MetS via retinol-dependent pathway and retinol-independent pathway, regardless of inflammatory status.[102] Alongside, Gavi et al. found that age should be regarded in the interpretation the link of RBP4 in obesity, as RBP4 level of obesity and IR are age dependent. There is a strong association of RBP4 levels with the components of MetS in young subjects compared with no or weak association in elderly.[103] In addition, childhood RBP4 may predict subsequent adult MetS, independent of pediatric obesity. Thus, adding childhood RBP4 level to the parts of MetS gives a more precise picture about risk and outcome of MetS.[104] Similarly, despite the same positive correlations between inflammatory biomarkers and obesity in both young and adults, RBP4 level in children with obesity and IR does not increase as in adults.[105] Recently, Majerczyk et al. revealed that RBP4 level in subjects older than 65 years is high and mainly correlated with high triglyceride levels and the feature of MetS independent of sex and renal function.[106] Regarding sexual dimorphism and risk of MetS, male subjects tend to have high risk of MetS compared with similarly aged premenopausal women in human and experimental animal model, since IR occurs rarely in female and commonly in male. In addition, a higher adiposity is required for female to induce metabolic disorders and MetS.[107] RBP4 level tends to be higher in male compared with female which might explain the higher risk of MetS in male subjects compared with matching women.[108] Therefore, in the implication of RBP4 in the development of MetS, age and gender should be concerned in relation to different cardiometabolic feature of MetS.


  Pharmacological Modulation of Retinol Binding Protein-4 Top


It is reasonable to verify that any drug or agent that inhibits RBP4 pathway might be of value as antiobesity or antidiabetic. Previously, Sasaki et al. reported that the regulation of RBP4 pathway is an important target for the prevention of T2DM and obesity via improvement of insulin sensitivity. Anthocyanin which is herbal derivative improves insulin sensitivity and hyperglycemia through reducting the expression of RBP4.[109] Similarly, both cinnamaldehyde and berberine, which are traditional Chinese medicine, have potent antidiabetic effect through improvement of insulin sensitivity and amelioration of IR in rats. These effects are due to upregulation of GLUT4 and reduction of RBP4 by an unknown mechanism.[110]

Effect of statins on retinol binding protein-4

The effect of statins on RBP4 plasma level is subjected to different controversies, previously Muggeo et al., found insignificant effect of statins therapy on RBP4 plasma level.[111] In addition, the effect of simvastatin 40 mg/day for 3 consecutive months produced an insignificant effect on RBP4 plasma levels.[112] Very little is known about the effect of statins on the RBP4 levels, due to the shortage of the prospective studies. Short duration and a small dose of statins might affect the results of different studies. Interestingly, RBP4-induced dyslipidemia is occurring via the activation of MTP. Therefore, MTP inhibitors might provide an alternative pathway to reduce LDL. Ezetimibe alone or in combination with an MTP inhibitor (AEGR-733) could be an effective combination to lower LDL in patients with statins intolerance.[113] Statins are not an effective inhibitor of hepatic MTP; thus, it ineffective in the management of homozygous familial hypercholesterolemia and does not affect RBP4-induced dyslipidemia.[114] In contrast, Aoki et al. found that both atorvastatin and pitavastatin inhibit intestinal MTP in rat, suggesting that these types of statins might interrupt the metabolic effect of RBP4 but not decrease it level.[115] It has been shown that epicardial adiposity is associated with different metabolic disorders due to high expression of RBP4 mRNA, and the reduction of epicardial fat thickness (EFT) might be an important way to reduce the cardiometabolic complications. Atorvastatin reduces EFT and RBP4 secretion as well as inflammatory and pro-inflammatory mediators which their levels are correlated with EFT.[116] Moreover, rosuvastatin improves insulin sensitivity, glucose tolerance, and fat distribution from visceral to subcutaneous adipose tissue, and by this pleotropic effect, it reduces visceral fat mass which is regarded as the main source of RBP4.[117] These findings give evidence for the effect of statins on RBP4 in different experimental and human studies. To the best of our knowledge, no direct effect of statins on RBP4 was reported; however, indirect effect is more applicable till time. Nevertheless, atorvastatin and simvastatin may potentiate the effect of RBP4 in the induction of IR, due to suppression of GLUT4 in cardiomyoctes.[118] Therefore, the potential effect of statins on the RBP4 and its metabolic effect remain controversial, and long-term prospective studies regarding the effect of statins on the level of RBP4 in patients with or without dyslipidemia are recommended.

The effect of fibrate on retinol binding protein-4

Fibrate drugs such as fenofibrate and gemfibrosil reduce circulating RBP4 plasma levels through suppression of RBP4 mRNA in the adipose tissue. A prospective study that describes the effect of 3-month therapy of fenofibrate on the circulating RBP4 showed that in the 1st month, RBP4 was increased due to the reduction in renal elimination of RBP4, but in the second 2 months, RBP4 level was decreased due to the inhibitory effect of fenofibrate on the expression of RBP4 MRNA in the adipose tissue.[119] Ong et al. study illustrated that long-term therapy with fenofibrate increases circulating RBP4 levels due to increase in the expression of PPARα, since PPARα agonists increase the production of RBP4 in brown adipose tissue (BAT). However, PPARα-knockout mice have lower hepatic RBP4.[120],[121] Moreover, fenofibrate and other PPARα agonists have been shown to ameliorate insulin sensitivity and reduce IR via activation of adiponectin mRNA in the adipose tissue. Adiponectin reduces RBP4-circulating levels through improvement of insulin signaling.[122] Therefore, fenofibrate reduces RBP4-circulating levels indirectly through adiponectin-dependent pathway as adiponectin level is inversely correlated with RBP4-circulating levels. Similarly, metabolic and anti-inflammatory effect of fenofibrate is mainly mediated by the elevation of adiponectin serum levels.[123]

It has been shown that visceral adiposity reduces adiponectin serum levels due to releasing of inflammatory biomarkers such as RBP4 and TNF-α, which inhibit the expression of adiponectin mRNA. Hence, activation of adiponectin mRNA by fenofibrate might suppress the activity of visceral adiposity and then the secretion of RBP4.[124]

Therefore, the metabolic effect of fenofibrate in the reduction of RBP4 is partly mediated by suppression of adipose tissue RBP4 mRNA and mainly by activation of adiponectin pathway.

The effect of thiazolidinediones on retinol binding protein-4

TZDs are a group of antidiabetic agents, act through activation of PPAR, and lead to a reduction of IR and improvement of adipocytes' insulin sensitivity. TZDs improve blood glucose, improve adipocyte lipid storage, and inhibit the production of adipocyte pro-inflammatory and inflammatory cytokines.[125] TZDs reduce circulating RBP4 levels via suppressing the expression of adipocytes RBP4 mRNA in patients with T2DM.[126] Pioglitazone improves IR through reduction of circulating RBP4 through reduction the expression of adipocyte mRNA of RBP4 but not hepatic mRNA of RBP4. Hepatic RBP4 is not associated with IR. The selective and differential effect of pioglitazone on the adipocytes rather than hepatocyte is due to overexpression of PPAR (in the adipocytes).[127] Therefore, this finding suggests that adipocytes' RBP4 is mainly involved in the pathogenesis of IR. Zhou et al. found that administration of pioglitazone in rats with impaired glucose tolerance leads to overexpression of RBP4 mRNA since direct effect of pioglitazone on cultured adipocyte increases lipogenesis and overexpression of RBP4 mRNA. In addition, lipogenesis increases the expression of RBP4 mRNA in a steady-state manner. As well, the activation of adipocyte differentiation by pioglitazone is mediated by PPARγ, thereby increasing RBP4 mRNA.[128] Conversely, the systemic effect of pioglitazone reduces adipocyte RBP4 mRNA, suggesting a different mechanism in the effect of pioglitazone on the circulating RBP4 levels. Alongside, Sell et al. demonstrated that troglitazone which is PPARγ agonist is ineffective in the reduction of RBP4 and other adipocytokines.[129] The beneficial effect of TZDs on the reduction of adipocyte RBP4 is linked to the reduction of diabetogenic pro-inflammatory mediators (TNF-α and IL-6) and improvement of adipocyte adiponectin mRNA expression and secretion.[130]

Normally, there are two types of adipose tissue, white adipose tissue (WAT) which stores energy and BAT which generates energy. Browning of WAT is occurring via activation of adipocyte gene, so WAT is converted into BAT and become as an energy source.[131] Recently, Krishnan et al. found that troglitazone leads to browning of WAT through activation of transient receptor potential vanilloid (TRPV1) which also activates PPAR. Therefore, troglitazone reduces the secretion source of RBP4 through a novel TRPV1/PPAR pathway.[132] In addition, troglitazone reduces IR through modulation of adipocyte genes and increases the differentiation of insulin-insensitive adipocytes to functionally mature insulin-sensitive adipocytes.[133]

Thus, the potential effect of TZDs on visceral adipose tissue is complicated and not simply mediated by inhibition of adipocyte RBP4 mRNA. Extensive molecular studies are recommended to explore the underlying hidden mechanisms of TZDs.

The effect of glucagon-like peptide 1 and dipeptidyl peptidase-IV inhibitors on retinol binding protein-4

It has been reported that both glucagon-like peptide 1 and dipeptidyl peptidase-IV inhibitors improve IR via modulation of RBP4-GLUT4 system.[134] Different experimental, preclinical, and clinical studies illustrated that GLP-1, sitagliptin, and vidagliptin might play a role in the reduction of IR through upregulation of GLUT4 in the adipocytes and skeletal muscles and inhibit the expression of adipocyte RBP4 mRNA. Upregulation of GLUT4 by sitagliptin is through inhibition MCP-1 which is a potent inhibitor of adipocyte GLUT4 and activation of adipocyte AMP-activated protein kinase pathways which increase adpiocyte GLUT4 translocation.[135],[136] Sun et al. also observed that sitagliptin improves IR in pregnant women with gestational diabetes through significant reduction of circulating RBP4 levels.[137] Thus, vildagliptin add-on metformin is more effective than metformin plus glimepiride combination in the amelioration of IR through suppression of RBP4 synthesis and secretion.[138] In addition, liraglutide, which is a GLP-1 receptor agonist, improves glycemic indices and reduces RBP4 through suppressing the expression of adipocyte RBP4 mRNA.[139] Han et al. found liraglutide add-on metformin therapy reduces RBP4 and other inflammatory adipose tissue-derived cytokine with significant elevation of adiponectin serum levels. These changes lead to indirect improvement of IR through elevation of insulin-sensitizing adiponectin in patients with T2DM.[140]

The effect of metformin on retinol binding protein-4

Metformin improves T2DM-induced dyslipidemia via the regulation of lipid metabolism, regulates the activity of lipoprotein lipase (LPL), reduces hepatic APO C-III (which is an inhibitor of LPL), reduces malonyl-CoA through AMP-activated, and accelerates hepatic β-oxidation.[141] Metformin also improves the activity and expression of adipocyte PPARα and reduces visceral fat mass, so metformin acts as PPARα agonist.[142] In addition, metformin increases translocation of GLUT4 at the adiopcyte cell membrane; herein, it improves adipocyte insulin sensitivity.[143] Therefore, metformin through these molecular mechanisms may reduce circulating RBP4 levels by different mechanisms including improvement of insulin sensitivity, upregulation of GLUT4, and activation of PPARα. Nonetheless, metformin may reduce RBP4 levels indirectly through stimulation of adiponectin.[144] Alternatively, RBP4 levels are elevated in women with polycystic ovary syndrome (PCOS) and correlated with lipid levels but not with IR. Metformin reduces both IR and RBP4, but this reduction is not correlated, suggesting that RBP4 levels are not a useful biomarker for IR in PCOS.[145] However, Brandauer et al. showed that metformin may impair the reduction of RBP4 by exercise training due to body adaptation and modulation of adipose tissue inflammatory pathways.[146] Therefore, these findings give evidence that metformin regulates adipose tissue inflammatory RBP4 directly or indirectly through modulation of IR and other cardiometabolic risk factors. Indeed, the addition of pioglitazone to metformin in patients with T2DM leads to more reduction in the level of RBP4, suggesting a synergistic effect of this combination on RBP4 serum levels.[147] Recently, Du et al. illustrated that metformin in combination with exenatide in obese patients with T2DM increases body fat redistribution. They increase subcutaneous adipose tissue (good fat) and reduce visceral adipose tissue (bad fat); thus, metformin may play an important role in the reduction the source of the synthesis of RBP4.[148] Similarly, metformin alone is also able to reduce central obesity and prevents the development of IR in the prepubertal children.[149]


  Conclusions Top


High circulating RBP4 levels are associated with different cardiometabolic disorders, including IR, T2DM, dyslipidemia, hypertension, HF, and ischemic stroke. Therefore, any drug that inhibits RBP4 pathway might be of value as antiobesity or antidiabetic. The potential effect of statins on the RBP4 and its metabolic effect remain controversial as it reduces RBP4; however, atorvastatin and simvastatin may potentiate the effect of RBP4 in the induction of IR, due to suppression of GLUT4 in cardiomyoctes. Fibrate drugs such as fenofibrate and gemfibrosil reduce circulating RBP4 plasma levels through suppression of RBP4 mRNA in adipose tissue. However, the metabolic effect of fenofibrate in the reduction of RBP4 is partly mediated by suppression of adipose tissue RBP4 and mainly by the activation of adiponectin pathway. Thus, the potential effect of TZDs on visceral adipose tissue is complicated and not simply mediated by inhibition of adipocyte RBP4 mRNA. DPPIV inhibitors and GLP-1 agonist reduce RBP4 and other inflammatory adipose tissue-derived cytokine with significant elevation of adiponectin serum levels. Metformin may reduce circulating RBP4 levels by different mechanisms including improvement of insulin sensitivity, upregulation of GLUT4, and activation of PPARα.

Acknowledgments

We would like to acknowledge Dr. Saad Al-den for his great supports.

Financial support and sponsorship

Nil.

Conflicts of interest

The authors declare that none of the authors have any competing interests.

Ethical conduct of research

This manuscript represents a literature review. Because this project involved no experimental design, the Institutional Review Board approval was not required. Applicable EQUATOR Network (http://www.equator-network.org) guidelines were followed.



 
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