Retinol-binding protein 4-transthyretin-retinol complex (Retinol/RBP4/TTR complex)

The Retinol/RBP4/TTR complex is a macromolecular assembly essential for the systemic transport of Vitamin A (retinol) in the blood. Retinol-binding protein 4 (RBP4) binds retinol in the liver and subsequently associates with transthyretin (TTR), a homotetrameric protein that also transports thyroxine. This association into a larger complex (~80 kDa) is critical because it prevents the small RBP4 protein (~21 kDa) from being rapidly cleared by glomerular filtration in the kidneys, thereby maintaining steady-state levels of circulating retinol (PMID: 26162397, 28212133). In clinical contexts, this complex is a therapeutic target for metabolic and ophthalmological diseases. Elevated levels of circulating RBP4 are strongly associated with insulin resistance, obesity, and type 2 diabetes, where it acts as an adipokine that impairs glucose uptake in muscle and increases hepatic glucose production (PMID: 16838004). In the eye, the delivery of retinol via this complex to the retinal pigment epithelium (RPE) leads to the formation of toxic bisretinoids (e.g., A2E), which are implicated in the progression of Stargardt disease and dry age-related macular degeneration. Drugs like Tinlarebant and Fenretinide work by disrupting the RBP4-TTR interaction or preventing retinol binding, thereby lowering serum RBP4 and retinol levels to reduce metabolic dysfunction or retinal toxin accumulation (PMID: 32694354, 30302251).

Other names

RBP4-TTR complexRetinol-RBP-TTR complexVitamin A transport complexPrealbumin-retinol binding protein complex

Disruption of the RBP4-TTR interaction to increase renal clearance of RBP4; inhibition of retinol binding to RBP4; reduction of circulating RBP4 levels; stabilization of TTR tetramer.