Biological Functions of RBP4 and Its Relevance for Human Diseases

Abstract

Retinol binding protein 4 (RBP4) is a member of the lipocalin family and the major transport protein of the hydrophobic molecule retinol, also known as vitamin A, in the circulation. Expression of RBP4 is highest in the liver, where most of the body's vitamin A reserves are stored as retinyl esters. For the mobilization of vitamin A from the liver, retinyl esters are hydrolyzed to retinol, which then binds to RBP4 in the hepatocyte. After associating with transthyretin (TTR), the retinol/RBP4/TTR complex is released into the bloodstream and delivers retinol to tissues via binding to specific membrane receptors. So far, two distinct RBP4 receptors have been identified that mediate the uptake of retinol across the cell membrane and, under specific conditions, bi-directional retinol transport. Although most of RBP4's actions depend on its role in retinoid homeostasis, functions independent of retinol transport have been described. In this review, we summarize and discuss the recent findings on the structure, regulation, and functions of RBP4 and lay out the biological relevance of this lipocalin for human diseases.

Keywords: RBP4; lipocalin; liver; metabolism; retinoids; retinol transport; vitamin A.

FIGURE 1

Hepatic retinol mobilization by RBP4. Most of liver retinoids are stored as retinyl esters in hepatic stellate cells in a LRAT-dependent manner. Upon hydrolysis by REH, retinol binds CRBP1 and becomes available to associate with RBP4 in hepatocytes. After complex formation with TTR, retinol/RBP4/TTR is secreted into the circulation. Both steps enhance secretion of the complex since depletion of retinol or TTR induces RBP4 accumulation in hepatocytes. Hepatocyte-expressed STRA6L is thought to confer reverse retinol transport from circulating holo-RBP4. Expression of Rbp4 mRNA is induced by cAMP/glucagon signaling and RBP4 protein translation enhanced by mTORC1 activation. Please note that pathways for uptake and storage of dietary retinoids from circulating lipoproteins, which are thought to be RBP4-independent, are not included in the figure. cAMP, cyclic adenosine monophosphate; CRBP1, cellular retinol binding protein 1; LRAT, lecithin retinol acyltransferase; mTORC1, mechanistic target of rapamycin in complex 1; RBP4, retinol binding protein 4; REH, retinyl ester hydrolases; STRA6L, stimulated by retinoic acid 6-like; TTR, transthyretin.

FIGURE 2

RBP4 membrane receptors for retinol transport. (A) Extrahepatic tissues including the eye take up retinol via binding of circulating holo-RBP4 to STRA6. Uptake is coupled to intracellular binding, storage and metabolism of retinol. STRA6 can also mediate efflux of cellular retinol to apo-RBP4, which was shown to be further stimulated by binding of calmodulin/Ca²⁺ to an intracellular domain of STRA6. (B) Liver, intestine, and several other organs but not the eye express STRA6L, predicted to have a similar transmembrane domain structure like STRA6. STRA6L catalyzes retinol uptake from holo-RBP4. Whether or not it can mediate bidirectional retinol transport, and how it couples to intracellular binding, storage and metabolism of retinol is currently unknown. RAR, retinoic acid receptor; RBP4, retinol binding protein 4; RXR retinoid X receptor; STRA6, stimulated by retinoic acid 6; STRA6L, stimulated by retinoic acid 6-like; TTR, transthyretin.

FIGURE 3

Proposed mechanisms for RBP4’s detrimental effects on insulin sensitivity. (A) RBP4, irrespective of its association with retinol and thus independent of retinol transport, was shown to activate TLR2/4 on inflammatory cells like macrophages. A downstream signaling cascade involving NFκB, JNK, and p38 leads to the secretion of IL1β and TNFα, which, in turn, impairs insulin signaling in adipocytes and leading to insulin resistance. (B) Binding of holo-RBP4 to STRA6 was shown to trigger tyrosine phosphorylation of the membrane receptor, resulting in recruitment and activation of JAK2 and the transcription factor STAT5. As a consequence, the induction of STAT5 target genes like Socs3 impairs insulin signaling. IL1β, interleukin 1β; JAK2, Janus kinase 2; JNK, c-Jun N-terminal kinases; NFκB, nuclear factor κ-B; MD2, myeloid differentiation protein-2; RBP4, retinol binding protein 4; Socs3, suppressor of cytokine signaling 3; STAT5, signal transducer and activator of transcription 5; STRA6, stimulated by retinoic acid 6; TNFα, tumor necrosis factor α; TLR2/4, toll-like receptors 2/4; TTR, transthyretin.