RBP4

Official Full Name

retinol binding protein 4

Organism

Homo sapiens

GeneID

5950

Background

This protein belongs to the lipocalin family and is the specific carrier for retinol (vitamin A alcohol) in the blood. It delivers retinol from the liver stores to the peripheral tissues. In plasma, the RBP-retinol complex interacts with transthyretin which prevents its loss by filtration through the kidney glomeruli. A deficiency of vitamin A blocks secretion of the binding protein posttranslationally and results in defective delivery and supply to the epidermal cells. [provided by RefSeq, Jul 2008]

Synonyms

RDCCAS; MCOPCB10;

Bio Chemical Class

Calycin family

Protein Sequence

MKWVWALLLLAALGSGRAERDCRVSSFRVKENFDKARFSGTWYAMAKKDPEGLFLQDNIVAEFSVDETGQMSATAKGRVRLLNNWDVCADMVGTFTDTEDPAKFKMKYWGVASFLQKGNDDHWIVDTDYDTYAVQYSCRLLNLDGTCADSYSFVFSRDPNGLPPEAQKIVRQRQEELCLARQYRLIVHNGYCDGRSERNLL

Open

Disease

Inherited retinal dystrophy

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

RBP4, a secreted member of the retinol-binding protein (RBP) family, consists of 181 amino acids and has a molecular weight of approximately 21 kDa. It contains a β-barrel domain that specifically binds one molecule of all-trans retinol, the active form of vitamin A. The RBP4 gene is located on chromosome 10q23-q24, and its three-dimensional structure has been resolved using X-ray diffraction. RBP4 is primarily synthesized by hepatocytes, accounting for over 80% of circulating protein, with adipose tissue contributing an additional 15–30%. Once bound to retinol, RBP4 forms a complex with thyroxine-binding protein (TTR) to stabilize its structure and is transported via the bloodstream to target tissues such as the retina and kidney. Cellular uptake of retinol is mediated by the STRA6 receptor on target cell membranes. RBP4 has a relatively short half-life of 3–12 hours, allowing it to sensitively reflect changes in liver and kidney function and serve as a dynamic biomarker for metabolic disorders or organ injury.

Metabolic Regulation and Disease Associations

RBP4 plays a critical role in metabolic regulation and is implicated in several diseases. In type 2 diabetes mellitus (T2DM), RBP4 acts as a key biomarker by inducing insulin resistance through inhibition of the IRS1/PI3K pathway in skeletal muscle, reducing GLUT4 translocation and impairing glucose uptake, while activating the JAK2/STAT5 pathway in adipose tissue to promote inflammatory cytokine release (TNF-α, IL-6). RBP4 can also directly damage pancreatic β-cells via STRA6-mediated activation of the JAK2/STAT1 pathway, inhibiting transcription factors such as Isl-1 and reducing insulin synthesis. Certain RBP4 gene polymorphisms (e.g., -803GA) further increase disease susceptibility, with elevated plasma levels reflecting β-cell dysfunction independently of HOMA-IR. RBP4 also contributes to non-alcoholic fatty liver disease (NAFLD) by downregulating genes involved in fatty acid oxidation, such as CPT1A, leading to hepatic lipid accumulation. In NAFLD mouse models, liver RBP4 mRNA expression is abnormally elevated and positively correlates with hepatic triglyceride content.

Figure 1. Molecular mechanisms by which RBP4 induces insulin resistance in skeletal muscle, liver, and adipose tissue. (Fan, et al., 2024)

Cardiovascular Disease Mechanisms

RBP4 is implicated in the development of atherosclerosis through multiple mechanisms. Elevated RBP4 levels are associated with systemic inflammation, potentially activating signaling pathways such as JNK and STAT1, promoting inflammatory cell activation and cytokine release, which exacerbates vascular wall inflammation and plaque formation. RBP4 may impair endothelial function, reducing endothelium-dependent vasodilation and increasing vascular tone and resistance, thereby creating conditions conducive to atherogenesis. It can also enhance cholesterol uptake and accumulation in macrophages, promoting foam cell formation, a central component of atherosclerotic plaques. Additionally, RBP4 may increase oxidative stress, causing damage to vascular endothelial and smooth muscle cells, lipid peroxidation, and oxidative modification of low-density lipoproteins, further accelerating plaque progression.

Vitamin A Transport and Physiological Function

RBP4 serves as the primary transporter of vitamin A in the body. In the liver, RBP4 binds all-trans retinol to form an RBP4-retinol complex, which associates with the plasma transport protein TTR to create a stable trimer that prevents renal filtration loss. This complex circulates through the bloodstream to target tissues such as the liver, intestine, and adipose tissue and is recognized by membrane receptors including STRA6 and the recently identified RBPR2, which contains transmembrane domains and is predominantly expressed in liver, intestine, and obese adipose tissue. Upon receptor binding, the complex undergoes endocytosis, releasing retinol in the acidic intracellular environment while RBP4-TTR is either recycled or degraded. RBPR2-mediated transport supports hepatic retinol storage and metabolic regulation, with expression negatively regulated by retinol and retinoic acid. In the retina, RPE cells release retinol via STRA6 to maintain photoreceptor function, and deficiencies lead to night blindness.

RBP4 as a Biomarker in Kidney Disease

Urinary RBP4 levels inversely correlate with glomerular filtration rate (GFR) and serve as a sensitive marker for early diabetic nephropathy and IgA nephropathy. Elevated urinary RBP4 (uRBP4) is observed in focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), and IgA nephropathy (IgAN), effectively predicting renal function decline. Studies have shown that uRBP4, in combination with other protein markers, can predict IgAN severity with high sensitivity and specificity. In FSGS patients, uRBP4 correlates positively with serum creatinine, proteinuria, and acute tubular-interstitial injury. Combinatorial analysis of uRBP4 and urinary SH3BGRL3 can distinguish between minimal change disease (MCD) and diabetic kidney disease (DKD). Chronic kidney dysfunction is also associated with elevated serum retinol and RBP4 levels, reflecting impaired renal handling of vitamin A.

Perspective

RBP4 plays a central role in the pathophysiology of metabolic and cardiovascular diseases by influencing insulin resistance, inflammation, oxidative stress, and lipid metabolism, and is closely associated with T2DM, NAFLD, atherosclerosis, coronary artery disease, and hypertension. Its function as a renal biomarker is increasingly recognized, with urinary RBP4 providing sensitive early detection of diabetic nephropathy and IgA nephropathy. The growing understanding of RBP4’s diverse roles offers insights into disease mechanisms and potential avenues for monitoring and therapeutic intervention.

Reference

Fan J, Hu J. Retinol binding protein 4 and type 2 diabetes: from insulin resistance to pancreatic β-cell function. Endocrine. 2024 Sep;85(3):1020-1034.
Steinhoff JS, Lass A, Schupp M. Biological Functions of RBP4 and Its Relevance for Human Diseases. Front Physiol. 2021 Mar 11;12:659977.

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