Significantly Reduced Retinol Binding Protein 4 (RBP4) Levels in Critically Ill COVID-19 Patients
Richard Vollenberg, Phil-Robin Tepasse, Manfred Fobker, Anna Hüsing-Kabar
Nutrients, doi:10.3390/nu14102007
The SARS-CoV-2 virus is the causative agent of the COVID-19 pandemic. The disease causes respiratory failure in some individuals accompanied by marked hyperinflammation. Vitamin A (syn. retinol) can exist in the body in the storage form as retinyl ester, or in the transcriptionally active form as retinoic acid. The main function of retinol binding protein 4 (RBP4), synthesized in the liver, is to transport hydrophobic vitamin A to various tissues. Vitamin A has an important role in the innate and acquired immune system. In particular, it is involved in the repair of lung tissue after infections. In viral respiratory diseases such as influenza pneumonia, vitamin A supplementation has been shown to reduce mortality in animal models. In critically ill COVID-19 patients, a significant decrease in plasma vitamin A levels and an association with increased mortality have been observed. However, there is no evidence on RBP4 in relation to COVID-19. This prospective, multicenter, observational, crosssectional study examined RBP4 (enzyme-linked immunosorbent assay) and vitamin A plasma levels (high-performance liquid chromatography) in COVID-19 patients, including 59 hospitalized patients. Of these, 19 developed critical illness (ARDS/ECMO), 20 developed severe illness (oxygenation disorder), and 20 developed moderate illness (no oxygenation disorder). Twenty age-matched convalescent patients following SARS-CoV-2 infection, were used as a control group. Reduced RBP4 plasma levels significantly correlated with impaired liver function and elevated inflammatory markers (CRP, lymphocytopenia). RBP4 levels were decreased in hospitalized patients with critical illness compared to nonpatients (p < 0.01). In comparison, significantly lower vitamin A levels were detected in hospitalized patients regardless of disease severity. Overall, we conclude that RBP4 plasma levels are significantly reduced in critically ill COVID-19 patients during acute inflammation, and vitamin A levels are significantly reduced in patients with moderate/severe/critical illness during the acute phase of illness.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: Data cannot be made public as personal patient data are included.
Conflicts of Interest: The authors declare no conflict of interest.
References
Aklamati, Mulenga, Dueker, Buchholz, Peerson et al., Accelerator mass spectrometry can be used to assess vitamin A metabolism quantitatively in boys in a community setting, J. Nutr,
doi:10.3945/jn.110.125500Aksoy, Karadag, Wollina, Angiotensin II receptors: Impact for COVID-19 severity, Dermatol. Ther
Bajzová, Kováčiková, Vítková, Klimčáková, Polák et al., Retinol-binding protein 4 expression in visceral and subcutaneous fat in human obesity, Physiol. Res,
doi:10.33549/physiolres.931379Broch, Vendrell, Ricart, Richart, Fernández-Real, Circulating retinol-binding protein-4, insulin sensitivity, insulin secretion, and insulin disposition index in obese and nonobese subjects, Diabetes Care,
doi:10.2337/dc06-2034Chen, Xiao, Hu, Ge, Tian et al., SARS-CoV-2 Nucleocapsid Protein Interacts with RIG-I and Represses RIG-Mediated IFN-β Production, Viruses,
doi:10.3390/v13010047Cho, Youn, Lee, Lee, Min et al., Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes, Diabetes Care,
doi:10.2337/dc06-0360Cummings, Baldwin, Abrams, Jacobson, Meyer et al., Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: A prospective cohort study, Lancet,
doi:10.1016/S0140-6736(20)31189-2Den Hollander, Mcgee, Ziviello, Banfi, Dryja et al., A homozygous missense mutation in the IRBP gene (RBP3) associated with autosomal recessive retinitis pigmentosa, Investig. Ophthalmol. Vis. Sci,
doi:10.1167/iovs.08-2497Du, Yang, Liu, Liu, COVID-19 and liver dysfunction: Epidemiology, association and potential mechanisms, Clin. Res. Hepatol. Gastroenterol,
doi:10.1016/j.clinre.2021.101793Erikstrup, Mortensen, Nielsen, Fischer, Plomgaard et al., RBP-to-retinol ratio, but not total RBP, is elevated in patients with type 2 diabetes, Diabetes Obes. Metab,
doi:10.1111/j.1463-1326.2008.00901.xFang, Karakiulakis, Roth, Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?, Lancet Respir. Med,
doi:10.1016/S2213-2600(20)30116-8Flach, Basten, Schreiner, Dietmann, Greco et al., Retinol binding protein 1 affects Xenopus anterior neural development via all-trans retinoic acid signaling, Dev. Dyn
Frey, Nagl, Henze, Raila, Schlosser et al., Isoforms of retinol binding protein 4 (RBP4) are increased in chronic diseases of the kidney but not of the liver, Lipids Health Dis
Frieman, Yount, Heise, Kopecky-Bromberg, Palese et al., Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane, J. Virol,
doi:10.1128/JVI.01012-07Fu, Gaelings, Jalovaara, Kakkola, Kinnunen et al., Protein profiling of nasopharyngeal aspirates of hospitalized and outpatients revealed cytokines associated with severe influenza A(H1N1)pdm09 virus infections: A pilot study, Cytokine,
doi:10.1016/j.cyto.2016.07.003Gieng, Green, Green, Rosales, Model-based compartmental analysis indicates a reduced mobilization of hepatic vitamin A during inflammation in rats, J. Lipid Res,
doi:10.1194/jlr.M600528-JLR200Hamming, Cooper, Haagmans, Hooper, Korstanje et al., The emerging role of ACE2 in physiology and disease, J. Pathol,
doi:10.1002/path.2162Hoffmann, Begon, Lafon, Duprey, Influence of glenohumeral joint muscle insertion on moment arms using a finite element model, Comput. Methods Biomech. Biomed. Eng,
doi:10.1080/10255842.2020.1789606Janke, Engeli, Boschmann, Adams, Böhnke et al., Retinol-binding protein 4 in human obesity, Diabetes,
doi:10.2337/db06-0616Jones, Oshansky, Bajracharya, Tang, Sun et al., Retinol binding protein and vitamin D associations with serum antibody isotypes, serum influenza virus-specific neutralizing activities and airway cytokine profiles, Clin. Exp. Immunol,
doi:10.1111/cei.12718Kessel, Vollenberg, Masjosthusmann, Hinze, Wittkowski et al., Discrimination of COVID-19 From Inflammation-Induced Cytokine Storm Syndromes Using Disease-Related Blood Biomarkers, Arthritis Rheumatol,
doi:10.1002/art.41763Krasinski, Cohn, Russell, Schaefer, Postprandial plasma vitamin A metabolism in humans: A reassessment of the use of plasma retinyl esters as markers for intestinally derived chylomicrons and their remnants, Metabolism
Kuba, Imai, Rao, Gao, Guo et al., A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury, Nat. Med,
doi:10.1038/nm1267Kumar, Kumar, Bedi, Gupta, Kumar et al., Role of vitamins and minerals as immunity boosters in COVID-19, Inflammopharmacology,
doi:10.1007/s10787-021-00826-7Muenzner, Tuvia, Deutschmann, Witte, Tolkachov et al., Retinol-binding protein 4 and its membrane receptor STRA6 control adipogenesis by regulating cellular retinoid homeostasis and retinoic acid receptor α activity, Mol. Cell. Biol,
doi:10.1128/MCB.00221-13Méry, Epaulard, Borel, Toussaint, Le Gouellec, COVID-19: Underlying Adipokine Storm and Angiotensin 1-7 Umbrella, Front. Immunol,
doi:10.3389/fimmu.2020.01714Nardo, Schneeweiss-Gleixner, Bakail, Dixon, Lax et al., Pathophysiological mechanisms of liver injury in COVID-19, Liver Int,
doi:10.1111/liv.14730Nawijn, Timens, Can ACE2 expression explain SARS-CoV-2 infection of the respiratory epithelia in COVID-19?, Mol. Syst. Biol,
doi:10.15252/msb.20209841Olsen, Blomhoff, Retinol, Retinoic Acid, and Retinol-Binding Protein 4 are Differentially Associated with Cardiovascular Disease, Type 2 Diabetes, and Obesity: An Overview of Human Studies, Adv. Nutr,
doi:10.1093/advances/nmz131Porzionato, Emmi, Barbon, Boscolo-Berto, Stecco et al., Sympathetic activation: A potential link between comorbidities and COVID-19, FEBS J,
doi:10.1111/febs.15481Ranieri, Rubenfeld, Thompson, Ferguson, Caldwell et al., Acute respiratory distress syndrome: The Berlin Definition, JAMA,
doi:10.1001/jama.2012.5669Roma, Krini, Hantzi, Sakka, Panayiotou et al., Retinol Binding Protein 4 in children with Inflammatory Bowel Disease: A negative correlation with the disease activity, Hippokratia
Sarohan, Kızıl, ˙inkaya, Mahmud, Akram et al., A novel hypothesis for COVID-19 pathogenesis: Retinol depletion and retinoid signaling disorder, Cell. Signal,
doi:10.1016/j.cellsig.2021.110121Shoemark, Colenso, Toelzer, Gupta, Sessions et al., Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS-CoV-2 Spike Protein**, Angew. Chem. Int. Ed. Engl,
doi:10.1002/anie.202015639Spiegel, Pichlmair, Martínez-Sobrido, Cros, García-Sastre et al., Inhibition of Beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor 3, J. Virol,
doi:10.1128/JVI.79.4.2079-2086.2005Tepasse, Hafezi, Lutz, Kühn, Wilms et al., Persisting SARS-CoV-2 viraemia after rituximab therapy: Two cases with fatal outcome and a review of the literature, Br. J. Haematol,
doi:10.1111/bjh.16896Tepasse, Vollenberg, Fobker, Kabar, Schmidt et al., Vitamin A Plasma Levels in COVID-19 Patients: A Prospective Multicenter Study and Hypothesis, Nutrients,
doi:10.3390/nu13072173Timoneda, Rodríguez-Fernández, Zaragozá, Marín, Cabezuelo et al., Vitamin A Deficiency and the Lung, Nutrients,
doi:10.3390/nu10091132Tsutsumi, Okuno, Tannous, Piantedosi, Allan et al., Retinoids and retinoid-binding protein expression in rat adipocytes, J. Biol. Chem
Ulgen, Herder, Kühn, Willenberg, Schott et al., Association of serum levels of retinol-binding protein 4 with male sex but not with insulin resistance in obese patients, Arch. Physiol. Biochem
Vollenberg, Matern, Nowacki, Fuhrmann, Padberg et al., Prone Position in Mechanically Ventilated COVID-19 Patients: A Multicenter Study, J. Clin. Med
Yang, Ye, Zhu, Wang, Deng et al., Middle East respiratory syndrome coronavirus ORF4b protein inhibits type I interferon production through both cytoplasmic and nuclear targets, Sci. Rep,
doi:10.1038/srep17554Yao-Borengasser, Varma, Bodles, Rasouli, Phanavanh et al., Retinol binding protein 4 expression in humans: Relationship to insulin resistance, inflammation, and response to pioglitazone, J. Clin. Endocrinol. Metab,
doi:10.1210/jc.2006-0816Zabetian-Targhi, Mahmoudi, Rezaei, Mahmoudi, Retinol binding protein 4 in relation to diet, inflammation, immunity, and cardiovascular diseases, Adv. Nutr,
doi:10.3945/an.115.008292Zhao, Meng, Kumar, Wu, Huang et al., Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A systemic review and meta-analysis, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2020.04.086Zhong, Huang, Yang, Li, Liu et al., Upregulation of angiotensin-converting enzyme 2 by all-trans retinoic acid in spontaneously hypertensive rats, Hypertension,
doi:10.1161/01.HYP.0000146400.57221.74Zhou, Wu, Qin, Yin, Association of all-trans retinoic acid treatment with the renin-angiotensin aldosterone system expression in glomerulosclerosis rats, J. Renin Angiotensin Aldosterone Syst,
doi:10.1177/1470320312465220
