Design, Synthesis, and Preclinical Efficacy of Novel Nonretinoid Antagonists of Retinol-Binding Protein 4 in the Mouse Model of Hepatic Steatosis

Cioffi, Christopher L.; Rácz, Bóglárka; Váradi, András; Freeman, Emily; Conlon, Michael P.; Chen, Ping; Zhu, Lei; Kitchen, Douglas B.; Barnes, Keith D.; Martin, William H.; Pearson, Paul G.; Johnson, Graham; Blaner, William S.; Petrukhin, Konstantin

doi:10.1021/acs.jmedchem.9b00352

Cited by 23 publications

(28 citation statements)

References 43 publications

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“…BPN-14136 is another non-retinoid compound that disrupts the RBP4 and TTR complex with the potential to treat atrophic age-related macular degeneration and Stargardt disease ( Cioffi et al, 2014 ). Interestingly, a BPN-14136 derivative was able to lower RBP4 and partially prevent high-fat diet induced obesity and hepatic steatosis in mice with adipose tissue-specific transgenic overexpression of human RBP4 described above ( Cioffi et al, 2019 ).…”

Section: Pharmacological Approaches To Lower Circulating Rbp4mentioning

confidence: 97%

“…This included palmitic acid, which could be purified from RBP4 in human urine ( Perduca et al, 2018 ). Moreover, palmitic and also linoleic acid, among others, were able to replace 3 H-retinol from human RBP4 ( Cioffi et al, 2019 ). Thus, RBP4 may be a physiologically relevant binding and transport protein for fatty acids.…”

Section: Interaction Of Rbp4 With Non-retinoid Ligandsmentioning

confidence: 99%

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Biological Functions of RBP4 and Its Relevance for Human Diseases

2021

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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.

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Section: Pharmacological Approaches To Lower Circulating Rbp4mentioning

confidence: 97%

Section: Interaction Of Rbp4 With Non-retinoid Ligandsmentioning

confidence: 99%

Biological Functions of RBP4 and Its Relevance for Human Diseases

2021

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“…[ 22 ] After RBP4 was released into blood, it binds to retinol and thyroxine carrier proteins and forms a retinol-RBP4-TTR ternary complex in the form of 1:1:1, which transports retinol to target tissues for specific physiological functions. [ 23 ] Early studies found that RBP4 was associated with fatty liver, glycolipid metabolic diseases such as diabetes mellitus and cardiovascular diseases. [ 4 , 24 ] It was deemed that RBP4 was a fat-derived factor in the blood and was considered as an important target for the treatment of type 2 diabetes mellitus (T2DM), insulin resistance, non-alcoholic fatty liver and visceral obesity.…”

Section: Discussionmentioning

confidence: 99%

Serum levels of retinol-binding protein 4 and the risk of non-small cell lung cancer

Hu¹,

Huang²,

Wang³

et al. 2020

Medicine

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Retinol binding protein 4 (RBP4), as an adipokine, has been identified to be associated with several types of cancer. However, no studies have assessed its effect on non-small cell lung cancer (NSCLC) risk. The objective of this study was to assess the association between serum RBP4 levels and the risk of NSCLC. A case-control study design was used to recruit 256 confirmed NSCLC cases and 256 age- and gender-matched healthy controls by frequency between August 2017 and January 2019. Serum RBP4 was measured using enzyme-linked immune absorbent assay before treatment. Unconditional logistic regression analysis was applied to estimate the odds ratio and 95% confidence interval (CI). Serum RBP4 level was significantly higher in NSCLC patients than those in the healthy control group (36.05 ± 8.28 vs 29.54 ± 7.71 μg/mL, P < .05). Higher serum RBP4 level was associated with increased risk of NSCLC ( P trend = .001). Compare with those in the lowest tertile, the adjusted odds ratios were 1.85 (95% CIs 1.07–3.2) ( P = .029) for the second tertile and 2.18 (95% CIs 1.37–3.45) ( P = .001) for the highest tertile after adjusting for confounding variables. No interactions were observed after stratified analyses by body mass index and smoking status ( P for interaction: .584 and .357). Our study indicated that serum RBP4 level was positively related to the risk of NSCLC. Additional studies with prospective design are required to confirm this finding.

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“…Accordingly, another study found fatty acids within the crystal structure of human retinol-free RBP4 isolated from serum, urine, and amniotic fluid [ 97 ]. Several fatty acids showed the capability of 3 H-retinol replacement in the binding pocket of human RBP4, providing another hint to the fatty acid binding and possible transporting function of RBP4 [ 98 ].…”

Section: Rbp4: a Carrier For Non-retinoid Ligands?mentioning

confidence: 99%

Retinoid Homeostasis and Beyond: How Retinol Binding Protein 4 Contributes to Health and Disease

2022

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Retinol binding protein 4 (RBP4) is the specific transport protein of the lipophilic vitamin A, retinol, in blood. Circulating RBP4 originates from the liver. It is secreted by hepatocytes after it has been loaded with retinol and binding to transthyretin (TTR). TTR association prevents renal filtration due to the formation of a higher molecular weight complex. In the circulation, RBP4 binds to specific membrane receptors, thereby delivering retinol to target cells, rendering liver-secreted RBP4 the major mechanism to distribute hepatic vitamin A stores to extrahepatic tissues. In particular, binding of RBP4 to ‘stimulated by retinoic acid 6’ (STRA6) is required to balance tissue retinoid responses in a highly homeostatic manner. Consequently, defects/mutations in RBP4 can cause a variety of conditions and diseases due to dysregulated retinoid homeostasis and cover embryonic development, vision, metabolism, and cardiovascular diseases. Aside from the effects related to retinol transport, non-canonical functions of RBP4 have also been reported. In this review, we summarize the current knowledge on the regulation and function of RBP4 in health and disease derived from murine models and human mutations.

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Design, Synthesis, and Preclinical Efficacy of Novel Nonretinoid Antagonists of Retinol-Binding Protein 4 in the Mouse Model of Hepatic Steatosis

Abstract: Retinol-binding protein 4 (RBP4) serves as a transporter for all-trans-retinol (1) in the blood, and it has been proposed to act as an adipokine. Elevated plasma levels of the protein have been linked *

Cited by 23 publications

References 43 publications

Biological Functions of RBP4 and Its Relevance for Human Diseases

Biological Functions of RBP4 and Its Relevance for Human Diseases

Serum levels of retinol-binding protein 4 and the risk of non-small cell lung cancer

Retinoid Homeostasis and Beyond: How Retinol Binding Protein 4 Contributes to Health and Disease

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