Exp Clin Endocrinol Diabetes 2024; 132(02): 91-97
DOI: 10.1055/a-2237-8863
Article

Bilirubin Down-Regulates Oxidative Stress and Fibroblast Growth Factor 23 Expression in UMR106 Osteoblast-Like Cells

Steffen Rausch
1   University of Hohenheim, Department of Physiology, Stuttgart, Germany
,
Katharina Hammerschmidt
1   University of Hohenheim, Department of Physiology, Stuttgart, Germany
,
Martina Feger
1   University of Hohenheim, Department of Physiology, Stuttgart, Germany
,
Libor Vítek
2   Fourth Department of Internal Medicine and Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
,
Michael Föller
1   University of Hohenheim, Department of Physiology, Stuttgart, Germany
› Author Affiliations
Funding Information Deutsche Forschungsgemeinschaft — http://dx.doi.org/10.13039/501100001659; Fo695/2–1

Abstract

Introduction Fibroblast growth factor 23 (FGF23) is a major regulator of phosphate and vitamin D metabolism in the kidney, and its higher levels in plasma are associated with poorer outcomes in kidney and cardiovascular diseases. It is produced by bone cells upon enhanced oxidative stress and inhibits renal phosphate reabsorption and calcitriol (active form of vitamin D) production. Bilirubin, the final product of the heme catabolic pathway in the vascular bed, has versatile biological functions, including antioxidant and anti-inflammatory effects. This study explored whether bilirubin alters FGF23 production.

Methods Experiments were performed using UMR106 osteoblast-like cells. Fgf23 transcript levels were determined by quantitative real-time polymerase chain reaction, C-terminal and intact FGF23 protein levels were determined by enzyme-linked immunosorbent assay, and cellular oxidative stress was assessed by CellROX assay.

Results Unconjugated bilirubin down-regulated Fgf23 gene transcription and FGF23 protein abundance; these effects were paralleled by lower cellular oxidative stress levels. Also, conjugated bilirubin reduced Fgf23 mRNA abundance.

Conclusion Bilirubin down-regulates FGF23 production in UMR106 cells, an effect likely to be dependent on the reduction of cellular oxidative stress.

Supplementary Material



Publication History

Received: 07 June 2023
Received: 14 December 2023

Accepted: 18 December 2023

Article published online:
19 February 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Bilha SC, Bilha A, Ungureanu M-C. et al. FGF23 beyond the kidney: A new bone mass regulator in the general population. Horm Metab Res 2020; 52: 298-304
  • 2 Yuan D, Li J, Guo M. et al. Correlation study of FGF23/D-serine in maintenance hemodialysis patients with combined hearing impairment. PLoS One 2023; 18: e0280378
  • 3 Ogunmoroti O, Osibogun O, Zhao D. et al. Associations between endogenous sex hormones and FGF-23 among women and men in the Multi-Ethnic Study of Atherosclerosis. PLoS One 2022; 17: e0268759
  • 4 Bergwitz C, Jüppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 2010; 61: 91-104
  • 5 Gattineni J, Bates C, Twombley K. et al. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 2009; 297: F282-F291
  • 6 Baum M, Schiavi S, Dwarakanath V. et al. Effect of fibroblast growth factor-23 on phosphate transport in proximal tubules. Kidney Int 2005; 68: 1148-1153
  • 7 Shimada T, Hasegawa H, Yamazaki Y. et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004; 19: 429-435
  • 8 Lu Y, Feng JQ. FGF23 in skeletal modeling and remodeling. Curr Osteoporos Rep 2011; 9: 103-108
  • 9 Xiao Z, Huang J, Cao L. et al. Osteocyte-specific deletion of Fgfr1 suppresses FGF23. PLoS One 2014; 9: e104154
  • 10 Leifheit-Nestler M, Große Siemer R, Flasbart K. et al. Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease. Nephrol Dial Transplant 2016; 31: 1088-1099
  • 11 Radhakrishnan K, Kim Y-H, Jung YS. et al. Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury. Proc Natl Acad Sci U S A 2021; 118: e2022841118
  • 12 Prié D, Forand A, Francoz C. et al. Plasma fibroblast growth factor 23 concentration is increased and predicts mortality in patients on the liver-transplant waiting list. PLoS One 2013; 8: e66182
  • 13 Smith ER, Tan S-J, Holt SG. et al. FGF23 is synthesised locally by renal tubules and activates injury-primed fibroblasts. Sci Rep 2017; 7: 3345
  • 14 Quarles LD. Fibroblast growth factor 23 and α-Klotho co-dependent and independent functions. Curr Opin Nephrol Hypertens 2019; 28: 16-25
  • 15 Kuro-O M. The FGF23 and Klotho system beyond mineral metabolism. Clin Exp Nephrol 2017; 21: 64-69
  • 16 Kuro-O M. A potential link between phosphate and aging—lessons from Klotho-deficient mice. Mech Ageing Dev 2010; 131: 270-275
  • 17 Chen C-D, Sloane JA, Li H. et al. The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci 2013; 33: 1927-1939
  • 18 Xie J, Cha S-K, An S-W. et al. Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun 2012; 3: 1238
  • 19 Maltese G, Karalliedde J. The putative role of the antiageing protein klotho in cardiovascular and renal disease. Int J Hypertens 2012; 2012: 757469
  • 20 Fliser D, Kollerits B, Neyer U. et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: The Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 2007; 18: 2600-2608
  • 21 Cornelissen A, Florescu R, Kneizeh K. et al. Fibroblast growth factor 23 and outcome prediction in patients with acute myocardial infarction. J Clin Med 2022; 11
  • 22 Plischke M, Neuhold S, Adlbrecht C. et al. Inorganic phosphate and FGF-23 predict outcome in stable systolic heart failure. Eur J Clin Invest 2012; 42: 649-656
  • 23 Takashi Y, Maeda Y, Toyokawa K. et al. Fibroblast growth factor 23 and kidney function in patients with type 1 diabetes. PLoS One 2022; 17: e0274182
  • 24 Chu C, Elitok S, Zeng S. et al. C-terminal and intact FGF23 in kidney transplant recipients and their associations with overall graft survival. BMC Nephrol 2021; 22: 125
  • 25 Hocher C-F, Chen X, Zuo J. et al. Fibroblast growth factor 23 is associated with the development of gestational diabetes mellitus. Diabetes Metab Res Rev 2023; 39: e3704
  • 26 Flamme I, Ellinghaus P, Urrego D. et al. FGF23 expression in rodents is directly induced via erythropoietin after inhibition of hypoxia inducible factor proline hydroxylase. PLoS One 2017; 12: e0186979
  • 27 Bär L, Feger M, Fajol A. et al. Insulin suppresses the production of fibroblast growth factor 23 (FGF23). Proc Natl Acad Sci USA 2018; 115: 5804-5809
  • 28 Glosse P, Fajol A, Hirche F. et al. A high-fat diet stimulates fibroblast growth factor 23 formation in mice through TNFα upregulation. Nutr Diabetes 2018; 8: 36
  • 29 Yamazaki M, Kawai M, Miyagawa K. et al. Interleukin-1-induced acute bone resorption facilitates the secretion of fibroblast growth factor 23 into the circulation. J Bone Miner Metab 2015; 33: 342-354
  • 30 Durlacher-Betzer K, Hassan A, Levi R. et al. Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease. Kidney Int 2018; 94: 315-325
  • 31 Voelkl J, Egli-Spichtig D, Alesutan I. et al. Inflammation: A putative link between phosphate metabolism and cardiovascular disease. Clin Sci (Lond) 2021; 135: 201-227
  • 32 Richter M, Schneider A, Maringanti R. et al. Transforming growth-factor-β is a potent inhibitor of FGF23 secretion from oncostatin M stimulated cardiomyocytes. Thorac Cardiovasc Surg 2016; 64(S 01): OP186
  • 33 Hori M, Kinoshita Y, Taguchi M. et al. Phosphate enhances Fgf23 expression through reactive oxygen species in UMR-106 cells. J Bone Miner Metab 2016; 34: 132-139
  • 34 Hanudel MR, Chua K, Rappaport M. et al. Effects of dietary iron intake and chronic kidney disease on fibroblast growth factor 23 metabolism in wild-type and hepcidin knockout mice. Am J Physiol Renal Physiol 2016; 311: F1369-F1377
  • 35 Rausch S, Barholz M, Föller M. et al. Vitamin A regulates fibroblast growth factor 23 (FGF23). Nutrition 2020; 79-80: 110988
  • 36 Glosse P, Feger M, Mutig K. et al. AMP-activated kinase is a regulator of fibroblast growth factor 23 production. Kidney Int 2018; 94: 491-501
  • 37 Vidal A, Rios R, Pineda C. et al. Direct regulation of fibroblast growth factor 23 by energy intake through mTOR. Sci Rep 2020; 10: 1795
  • 38 Bär L, Hase P, Föller M. PKC regulates the production of fibroblast growth factor 23 (FGF23). PLoS One 2019; 14: e0211309
  • 39 Sullivan JI, Rockey DC. Diagnosis and evaluation of hyperbilirubinemia. Curr Opin Gastroenterol 2017; 33: 164-170
  • 40 Vítek L. Bilirubin as a signaling molecule. Med Res Rev 2020; 40: 1335-1351
  • 41 Vítek L, Ostrow JD. Bilirubin chemistry and metabolism; harmful and protective aspects. Curr Pharm Des 2009; 15: 2869-2883
  • 42 Roche SP, Kobos R. Jaundice in the adult patient. Am Fam Physician 2004; 69: 299-304
  • 43 Bulmer AC, Verkade HJ, Wagner K-H. Bilirubin and beyond: A review of lipid status in Gilbert’s syndrome and its relevance to cardiovascular disease protection. Prog Lipid Res 2013; 52: 193-205
  • 44 Ihara H, Hashizume N, Shimizu N. et al. Threshold concentration of unbound bilirubin to induce neurological deficits in a patient with type I Crigler-Najjar syndrome. Ann Clin Biochem 1999; 36: 347-352
  • 45 Ehlers L, Netz LAW, Reiner J. et al. Effects of bile duct ligation and ghrelin treatment on the colonic barrier and microbiome of mice. Pharmacology 2022; 107: 564-573
  • 46 Vítek L. Bilirubin and atherosclerotic diseases. Physiol Res 2017; 66: S11-S20
  • 47 Bosma PJ, Chowdhury JR, Bakker C. et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 1995; 333: 1171-1175
  • 48 Vítek L. Bilirubin as a predictor of diseases of civilization. Is it time to establish decision limits for serum bilirubin concentrations?. Arch Biochem Biophys 2019; 672: 108062
  • 49 Ziberna L, Martelanc M, Franko M. et al. Bilirubin is an endogenous antioxidant in human vascular endothelial cells. Sci Rep 2016; 6: 29240
  • 50 Vitek L, Hinds TD, Stec DE. et al. The physiology of bilirubin: Health and disease equilibrium. Trends Mol Med 2023;
  • 51 Vítek L, Tiribelli C. Bilirubin: The yellow hormone?. J Hepatol 2021; 75: 1485-1490
  • 52 Domazetovic V, Falsetti I, Ciuffi S. et al. Effect of oxidative stress-induced apoptosis on active FGF23 levels in MLO-Y4 cells: The protective role of 17-β-estradiol. Int J Mol Sci 2022; 23: 2103
  • 53 Lang F, Leibrock C, Pandyra AA. et al. Phosphate homeostasis, inflammation and the regulation of FGF-23. Kidney Blood Press Res 2018; 43: 1742-1748
  • 54 Stec DE, John K, Trabbic CJ. et al. Bilirubin binding to PPARα inhibits lipid accumulation. PLoS One 2016; 11: e0153427
  • 55 Ewendt F, Hirche F, Feger M. et al. Peroxisome proliferator-activated receptor α (PPARα)-dependent regulation of fibroblast growth factor 23 (FGF23). Pflügers Archiv 2020; 472: 503-511
  • 56 DiNicolantonio JJ, McCarty MF, O’Keefe JH. Antioxidant bilirubin works in multiple ways to reduce risk for obesity and its health complications. Open Heart 2018; 5: e000914
  • 57 Maruhashi T, Soga J, Fujimura N. et al. Hyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in Gilbert syndrome. Circulation 2012; 126: 598-603
  • 58 Hana CA, Klebermass E-M, Balber T. et al. Inhibition of lipid accumulation in skeletal muscle and liver cells: A protective mechanism of bilirubin against diabetes mellitus type 2. Front Pharmacol 2020; 11: 636533
  • 59 Wallner M, Marculescu R, Doberer D. et al. Protection from age-related increase in lipid biomarkers and inflammation contributes to cardiovascular protection in Gilbert’s syndrome. Clin Sci (Lond) 2013; 125: 257-264
  • 60 Faul C, Amaral AP, Oskouei B. et al. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121: 4393-4408
  • 61 Lee Y, Kim H, Kang S. et al. Bilirubin nanoparticles as a nanomedicine for anti-inflammation therapy. Angew Chem Int Ed Engl 2016; 55: 7460-7463
  • 62 Roy-Chowdhury N, Wang X, Roy-Chowdhury J. Bile Pigment Metabolism and Its Disorders. In: Emery and Rimoin’s principles and practice of medical genetics and genomics. Elsevier; 2020: 507-553
  • 63 Vítek L, Schwertner HA. The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases. Adv Clin Chem 2007; 43: 1-57
  • 64 Vogel ME, Zucker SD. Bilirubin acts as an endogenous regulator of inflammation by disrupting adhesion molecule-mediated leukocyte migration. Inflamm Cell Signal 2016; 3: e1178
  • 65 Francis C, David V. Inflammation regulates fibroblast growth factor 23 production. Curr Opin Nephrol Hypertens 2016; 25: 325-332
  • 66 Huang J, Zhao Q, Li J. et al. Correlation between neonatal hyperbilirubinemia and vitamin D levels: A meta-analysis. PLoS One 2021; 16: e0251584
  • 67 van der Veere CN, Schoemaker B, Bakker C. et al. Influence of dietary calcium phosphate on the disposition of bilirubin in rats with unconjugated hyperbilirubinemia. Hepatology 1996; 24: 620-626