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

Steffen Rausch; Katharina Hammerschmidt; Martina Feger; Libor Vítek; Michael Föller

doi:10.1055/a-2237-8863

Experimental and Clinical Endocrinology & Diabetes, Inhaltsverzeichnis

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

¹University of Hohenheim, Department of Physiology, Stuttgart, Germany

,

Katharina Hammerschmidt

¹University of Hohenheim, Department of Physiology, Stuttgart, Germany

,

Martina Feger

¹University of Hohenheim, Department of Physiology, Stuttgart, Germany

,

Libor Vítek

²Fourth 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

¹University of Hohenheim, Department of Physiology, Stuttgart, Germany

› Institutsangaben

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.

Key words

Klotho - ROS - phosphate

Volltext

Referenzen

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

Zusatzmaterial

Supplementary Material