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Retinol Binding Protein-4 Signaling Pathway


Figure 1. Retinol binding protein-4 signaling pathway.

Retinol binding protein-4 overview

Retinol-binding protein 4 (RBP4), the sole retinol transporter in blood, is secreted from adipocytes and liver. Retinol (vitamin A) plays an important role in promoting the steady state of the animal's body. Its lack can lead to diseases such as night blindness and can lead to the reduction of energy resources and cell membrane destruction of embryos or eggs and affect the quality of embryos and eggs. Retinol-binding protein 4 (RBP4) is a member of the retinol-binding protein (RBP) family. The storage, absorption, and transport of retinol in the body must depend on the presence of RBP4, which is the only one that has been confirmed so far. A transporter that transports retinol in the blood, the main expression site is the liver, and other organs such as the kidney are also expressed. RBP4 can transport retinol and its active metabolites from the liver to the target tissue, assisting retinol to exert its physiological effects. RBP4 acts as a cellular messenger from fat cells. If it is lacking in the body, it will cause confusion in the distribution of retinol in tissues, which will affect the growth, differentiation, reproduction and embryonic development of bone and epithelial tissues, and further lead to diseases such as night blindness. For humans, RBP4 levels are reduced with retinol (VitA) deficiency, hypoproteinemia, malabsorption syndrome, liver disease (except over-nutrition fatty liver), hyperthyroidism, etc.; RBP4 decline in serum can also cause acute and chronic hepatitis and cirrhosis. If the RBP4 content in the body is higher than the threshold, it will cause renal insufficiency and overnutrition. Studies have reported that serum RBP4 levels are associated with multiple metabolic parameters such as waist circumference, BMI, and TG. More studies now suggest that RBP4, as a cytokine, can participate in the process of obesity, type 2 diabetes, and insulin resistance by regulating lipid metabolism. At the same time, RBP4 plays a role in the pathogenesis of sex hormone-related diseases. Serum RBP4 levels are positively correlated with testosterone and negatively correlated with sex hormone binding protein (SHBG) and are higher in men than in women.

Retinol binding protein-4 family

RBP4 is an adipocytokine detected in 2005 by scientists Yang using gene chip technology. The essence of RBP4 is a small molecule combination protein with hydrophobic properties, which is one of many transgenic proteins with the ability to transport fat-soluble vitamins. A protein consisting of 184 amino acids with a relative molecular mass of 21kD and the entire molecule consists of an N-terminal loop, a β-barrel structure, an alpha helix and a C-terminal loop. Its gene is located near chromosome 10 (10q23-q24). RBP4 is mainly synthesized by the liver, but its mRNA can be expressed in various extrahepatic tissues such as adipose tissue, kidney and lung. The key role of RBP4 is to transport hydrophobic retinol from the liver to peripheral tissues to complete the transport of vitamin A from the liver to the target tissue. RBP4 not only interacts with retinol, but also forms a polymer compound in a specific ratio with retinol or thyroxine combined globulin (TBG). Such a combination of structures enhances the stability of the retinol structure, minimizes the probability of specific oxidation of retinol, significantly reduces its toxic effects, and prevents small molecule retinol from glomerular filtration.

Retinol binding protein-4 signaling pathway

  1. Retinol binding protein-4 signaling pathway cascade
    RBP4 induces expression of proinflammatory cytokines in mouse and human macrophages and thereby indirectly inhibits insulin signaling in cocultured adipocytes. This occurs through activation of c-Jun N-terminal protein kinase (JNK) and Toll-like receptor 4 (TLR4) pathways independent of the RBP4 receptor, STRA6. RBP4 effects are markedly attenuated in JNK macrophages and TLR4 macrophages. Retinol-free RBP4 (apo-RBP4) is as potent as retinol-bound RBP4 (holo-RBP4) in inducing proinflammatory cytokines in macrophages. Apo-RBP4 is likely to be physiologically significant since RBP4/retinol ratios are increased in serum of lean and obese insulin-resistant humans compared to ratios in insulin-sensitive humans, indicating that higher apo-RBP4 is associated with insulin resistance independent of obesity. Thus, RBP4 may cause insulin resistance by contributing to the development of an inflammatory state in adipose tissue through activation of proinflammatory cytokines in macrophages. This process reveals a novel JNK- and TLR4-dependent and retinol- and STRA6-independent mechanism of action for RBP4.
  2. Pathway regulation
    Association of RBP-retinol with STRA6 triggers tyrosine phosphorylation, resulting in recruitment and activation of JAK2 and the transcription factor STAT5. The RBP– retinol/STRA6/JAK2/STAT5 signaling cascade induces the expression of STAT target genes, including suppressor of cytokine signaling 3 (SOCS3), which inhibits insulin signaling, and peroxisome proliferator-activated receptor gamma (PPARγ), which enhances lipid accumulation. BPR-4 protein can be used as an independent biomarker of many diseases, so the normal content of BPR-4 protein is particularly important for the maintenance of homeostasis. Many domestic and foreign studies have shown that BPR-4 protein in the IGR state of the body was significantly increased, and the BPR-4 signaling pathway is significantly enhanced. In addition to indicating that BPR-4 can be used as an indicator of related diseases, it can also be explained that the BPR-4 signaling pathway in the body is regulated by the health status of the body.
  3. Relationship with disease
    Coronary heart disease
    The level of BPR4 in patients with coronary heart disease was significantly higher than that in the control group. Regression analysis showed that BPR4 was a risk factor for coronary heart disease. At present, some progress has been made in the study of the specific mechanism of BPR4 involvement in the occurrence and development of coronary heart disease. It is expected to become an effective means of treating coronary heart disease in the future.
    Diabetes
    Studies have shown that the expression of RBP4 in the serum of patients with diabetes mellitus complicated with coronary heart disease is significantly higher than that of the normal control group, and it is also significantly higher than that of the simple coronary heart disease group, suggesting that RBP4 is involved in the occurrence of diabetes mellitus with coronary heart disease, and related research results at home and abroad are consistent.

References:

  1. Zabetiantarghi F, Mahmoudi M J, Rezaei N, et al. Retinol Binding Protein 4 in Relation to Diet, Inflammation, Immunity, and Cardiovascular Diseases. Advances in Nutrition. 2015, 6(6):748-62.
  2. Tanik N, Celikbilek A, Metin A, et al. Retinol-binding protein-4 and hs-CRP levels in patients with migraine. Neurological Sciences. 2015, 36(10):1823-1827.
  3. Ram J, Snehalatha C, Selvam S, et al. Retinol binding protein-4 predicts incident diabetes in Asian Indian men with prediabetes. Biofactors. 2015, 41(3):160-165.
  4. Ferraz-Amaro I, González-Gay M A, Diaz-González F. Retinol-binding protein 4 in rheumatoid arthritis-related insulin resistance and β-cell function. Journal of Rheumatology. 2014, 41(4):658-665.
  5. Abola M V, Thompson C L, Zhengyi C, et al. Serum levels of retinol-binding protein 4 and risk of colon adenoma. Endocrine-related cancer. 2015, 22(2):1-4.

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