Prophylactic Fucose can Alleviate Lipopolysaccharide-Induced Cholestatic Liver Injury in Neonatal RatsFunding The study was financially supported by TUBITAK (Project Number: 115S953).
12 March 2019
25 June 2019
13 August 2019 (online)
Objectives Cholestasis is a common disease of the liver in premature infants and no specific preventive treatment is currently available. Fucose, one of the monosaccharide building blocks of human milk oligosaccharides, may prevent cholestatic hepatic injury by various mechanisms. The aim of this study was to investigate the protective effect of fucose treatment after endotoxin-induced cholestasis in a rat model.
Methods Wistar rat pups were divided into four groups as: group I, control group; group II, fucose-supplemented group; group III, lipopolysaccharide (LPS)-administered group, and group IV, LPS-exposed and fucose-supplemented group. Fucose was given 100 mg/kg i.p. every other day between PN5–17. LPS was administered on PN19 to establish endotoxin-induced cholestasis model. On PN21, animals were sacrificed to evaluate liver cell damage and apoptosis.
Results Fucose supplementation significantly improved the biochemical parameters that deteriorated in LPS-administered group, significantly increased the expression of bile salt export pump, reduced the number of apoptotic cell death, and greatly prevented LPS-induced cholestatic hepatic injury.
Conclusion Given our results, fucose may be useful in reducing hepatic injury and might possess clinical relevance for the preventive treatment of inflammation-induced cholestatic injury in newborns.
This study was conducted in the Neonatology Department of Dokuz Eylul University School of Medicine, Izmir, Turkey. Any affiliations with or involvement in any organization or entity with direct financial interest in the subject matter or materials discussed in the manuscript are disclosed in the paper.
- 1 Lane E, Murray KF. Neonatal Cholestasis. PediatrClin North Am 2017; 64 (03) 621-639
- 2 Zong Y, Stanger BZ. Molecular mechanisms of bile duct development. Int J Biochem Cell Biol 2011; 43 (02) 257-264
- 3 Sparks EE, Huppert KA, Brown MA, Washington MK, Huppert SS. Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice. Hepatology 2010; 51 (04) 1391-1400
- 4 Lewis T, Kuye S, Sherman A. Ursodeoxycholic acid versus phenobarbital for cholestasis in the neonatal intensive care unit. BMC Pediatr 2018; 18 (01) 197
- 5 Champion V, Carbajal R, Lozar J, Girard I, Mitanchez D. Risk factors for developing transient neonatal cholestasis. J Pediatr Gastroenterol Nutr 2012; 55 (05) 592-598
- 6 Dani C, Pratesi S, Raimondi F, Romagnoli C. ; Task Force for Hyperbilirubinemia of the Italian Society of Neonatology. Italian guidelines for the management and treatment of neonatal cholestasis. Ital J Pediatr 2015; 41: 69
- 7 Varshney S, Stanley P. Multiple roles for O-glycans in notch signalling. FEBS Lett 2018; 592 (23) 3819-3834
- 8 Schneider M, Al-Shareffi E, Haltiwanger RS. Biological functions of fucose in mammals. Glycobiology 2017; 27 (07) 601-618
- 9 Kumral A. , et al. A spoonful of sugar for neonatal cholestasis: Enhancement of fucosylation may act through lectins and notch pathway. J Clin Neonatol 2014; 3 (04) 236
- 10 Werz DB, Ranzinger R, Herget S, Adibekian A, von der Lieth CW, Seeberger PH. Exploring the structural diversity of mammalian carbohydrates (“glycospace”) by statistical databank analysis. ACS Chem Biol 2007; 2 (10) 685-691
- 11 Lowe JB. Selectin ligands, leukocyte trafficking, and fucosyl transferase genes. Kidney Int 1997; 51 (05) 1418-1426
- 12 Cuperus FJ, Claudel T, Gautherot J, Halilbasic E, Trauner M. The role of canalicular ABC transporters in cholestasis. Drug Metab Dispos 2014; 42 (04) 546-560
- 13 Kim MJ, Kang YJ, Kwon M. , et al. Ursodeoxycholate restores biliary excretion of methotrexate in rats with ethinyl estradiol induced-cholestasis by restoring canalicular mrp2 expression. Int J Mol Sci 2018; 19 (04) E1120
- 14 Keppler D. The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia. Drug Metab Dispos 2014; 42 (04) 561-565
- 15 Clouston AD. Pathologic features of hereditary cholestatic Diseases. Surg Pathol Clin 2018; 11 (02) 313-327
- 16 Wetzel W, Popov N, Lössner B, Schulzeck S, Honza R, Matthies H. Effect of L-fucose on brain protein metabolism and retention of a learned behavior in rats. Pharmacol Biochem Behav 1980; 13 (06) 765-771
- 17 Choi SS, Lynch BS, Baldwin N. , et al. Safety evaluation of the human-identical milk monosaccharide, l-fucose. Regul Toxicol Pharmacol 2015; 72 (01) 39-48
- 18 Laschke MW, Menger MD, Wang Y, Lindell G, Jeppsson B, Thorlacius H. Sepsis-associated cholestasis is critically dependent on P-selectin-dependent leukocyte recruitment in mice. Am J Physiol Gastrointest Liver Physiol 2007; 292 (05) G1396-G1402
- 19 Dold S, Laschke MW, Zhau Y. , et al. P-selectin glycoprotein ligand-1-mediated leukocyte recruitment regulates hepatocellular damage in acute obstructive cholestasis in mice. Inflamm Res 2010; 59 (04) 291-298
- 20 Jafar-Nejad H, Leonardi J, Fernandez-Valdivia R. Role of glycans and glycosyltransferases in the regulation of Notch signaling. Glycobiology 2010; 20 (08) 931-949
- 21 Lühn K, Wild MK. Human deficiencies of fucosylation and sialylation affecting selectin ligands. Semin Immunopathol 2012; 34 (03) 383-399
- 22 Mehta-D'souza P, Klopocki AG, Oganesyan V. , et al. Glycan bound to the selectin low affinity state engages Glu-88 to stabilize the high affinity state under force. J Biol Chem 2017; 292 (06) 2510-2518
- 23 Tanimizu N, Kaneko K, Itoh T. , et al. Intrahepatic bile ducts are developed through formation of homogeneous continuous luminal network and its dynamic rearrangement in mice. Hepatology 2016; 64 (01) 175-188
- 24 Annani-Akollor ME, Wang S, Fan J, Liu L, Padhiar AA, Zhang J. Downregulated protein O-fucosyl transferase 1 (Pofut1) expression exerts antiproliferative and antiadhesive effects on hepatocytes by inhibiting Notch signalling. Biomed Pharmacother 2014; 68 (06) 785-790
- 25 Hidalgo A, Frenette PS. Enforced fucosylation of neonatal CD34+ cells generates selectin ligands that enhance the initial interactions with microvessels but not homing to bone marrow. Blood 2005; 105 (02) 567-575