Abstract
Background
Hepatic hypoxia always results in liver inflammation and dysfunction. Fatty acid-binding protein 5 (FABP5) has been reported as a hypoxia-inducible gene and a regulator of inflammatory reaction.
Objective
To evaluate the effects of FABP5 on hypoxic liver injury and its potential mechanisms.
Results
FABP5 was hypoxia-inducible expression in liver tissues and LO2 cells. The expression levels of IL6 and TNFα were upregulated with the increasing expression of FABP5 in LO2 cells. Downregulation of FABP5 expression decreased the expression levels of ALT, AST and increased cell viability of hypoxic LO2 cells. Downregulation of FABP5 expression inhibited the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway and decreased inflammatory reaction in hypoxic LO2 cells.
Conclusions
FABP5 was shown to activate COX-2/PGE2 pathway and promote hypoxic injury in LO2 cells. FABP5 may be a potential target for the treatment of hypoxic liver injury.
Similar content being viewed by others
References
Abe Y, Uchinami H, Kudoh K et al (2012) Liver epithelial cells proliferate under hypoxia and protect the liver from ischemic injury via expression of HIF-1 alpha target genes. Surgery 152:869–878
Armstrong EH, Goswami D, Griffin PR, Noy N, Ortlund EA (2014) Structural basis for ligand regulation of the fatty acid-binding protein 5, peroxisome proliferator-activated receptor β/δ (FABP5-PPARβ/δ) signaling pathway. J Biol Chem 289(21):14941–14954
Bilzer M, Gerbes AL (2002) Pivotal role of G-protein–coupled adenosine A2a receptors in protection of the liver against inflammation and ischemia-reperfusion injury. Hepatology 36:1009–1011
Bogdan D, Falcone J, Kanjiya MP et al (2018) Fatty acid-binding protein 5 controls microsomal prostaglandin E synthase 1 (mPGES-1) induction during inflammation. J Biol Chem 293:5295–5306
Colville-Nash PR, Gilroy DW (2000) COX-2 and the cyclopentenone prostaglandins - a new chapter in the book of inflammation? Prostaglandins Other Lipid Mediat 62:33–43
da Rosa DP, Forgiarini LF, Baronio D, Feijó CA, Martinez D, Marroni NP (2012) Simulating sleep apnea by exposure to intermittent hypoxia induces inflammation in the lung and liver. Med Inflam 2012:879419
Davies NM, Mclachlan AJ, Day RO, Williams KM (2000) Clinical pharmacokinetics and pharmacodynamics of celecoxib. Clin Pharmacokinet 38:225–242
Echizen K, Hirose O, Maeda Y, Oshima M (2016) Inflammation in gastric cancer: interplay of the COX-2/prostaglandin E2 and Toll-like receptor/MyD88 pathways [published correction appears in Cancer Sci. 2016 Jul; 107(7):1059]. Cancer Sci 107:391–397
Farombi EO, Shrotriya S, Surh YJ (2009) Kolaviron inhibits dimethyl nitrosamine-induced liver injury by suppressing COX-2 and iNOS expression via NF-kappaB and AP-1. Life Sci 84:149–155
Han Q, Yeung SC, Ip MSM, Mak JCW (2010) Effects of intermittent hypoxia on A-/E-FABP expression in human aortic endothelial cells. Int J Cardiol 145:396–398
Haunerland NH, Spener F (2004) Fatty acid-binding proteins–insights from genetic manipulations. Prog Lipid Res 43(4):328–349
Hohoff C, Börchers T, Rüstow B, Spener F, van Tilbeurgh H (1999) Expression, purification, and crystal structure determination of recombinant human epidermal-type fatty acid binding protein. Biochemistry 38:12229–12239
Khan AA, Iadarola M, Yang HYT (2007) Dionne RA. Expression of COX-1 and COX-2 in a clinical model of acute inflammation. J Pain 8:349–354
Kreiss C, Birder LA, Kiss S, VanBibber MM, Bauer AJ (2003) COX-2 dependent inflammation increases spinal Fos expression during rodent postoperative ileus. Gut 52:527–534
Lee IT, Lin CC, Lin WN et al (2013) Lung inflammation caused by adenosine-5’-triphosphate is mediated via Ca2+/PKCs-dependent COX-2/PGE2 induction. Int J Biochem Cell Biol 45(8):1657–1668
Lefere S, Van Steenkiste C, Verhelst X, Van Vlierberghe H, Devisscher L, Geerts A (2016) Hypoxia-regulated mechanisms in the pathogenesis of obesity and non-alcoholic fatty liver disease. Cell Mol Life Sci 73(18):3419–3431
Lin BR, Yu CJ, Chen WC et al (2009) Green tea extract supplement reduces D-galactosamine-induced acute liver injury by inhibition of apoptotic and proinflammatory signaling. J Biomed Sci 16:35
Moore SM, Holt VV, Malpass LR, Hines IN, Wheeler MD (2015) Fatty acid-binding protein 5 limits the anti-inflammatory response in murine macrophages. Mol Immunol 67:265–275
Ohata H, Kinaret P, Kilpeläinen M et al (2015) Level of fatty acid binding protein 5 (FABP5) is increased in sputum of allergic asthmatics and links to airway remodeling and inflammation. PLoS ONE 10:e0127003
Ohata T, Yokoo H, Kamiyama T et al (2017) Fatty acid-binding protein 5 function in hepatocellular carcinoma through induction of epithelial-mesenchymal transition. Cancer Med 6(5):1049–1061
Rao D, Perraud AL, Schmitz C, Gally F (2017) Cigarette smoke inhibits LPS-induced FABP5 expression by preventing c-Jun binding to the FABP5 promoter. PLoS ONE 12:e0178021
Rosmorduc O, Housset C (2010) Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease. Semin Liver Dis 30(3):258–270
Suematsu M, Suzuki H, Ishii H et al (1992) Topographic dissociation between mitochondrial dysfunction and cell death during low-flow hypoxia in perfused rat liver. Lab Invest 67:434–442
van der Graaff D, Kwanten WJ, Francque SM (2019) The potential role of vascular alterations and subsequent impaired liver blood flow and hepatic hypoxia in the pathophysiology of non-alcoholic steatohepatitis. Med Hypotheses 122:188–197
Wei X, Tang C, Lu X et al (2015) MiR-101 targets DUSP1 to regulate the TGF-β secretion in sorafenib inhibits macrophage-induced growth of hepatocarcinoma. Oncotarget 6:18389–18405
Xiong X, Ren Y, Cui Y, Li R, Wang C, Zhang Y (2017) Obeticholic acid protects mice against lipopolysaccharide-induced liver injury and inflammation. Biomed Pharmacother 96:1292–1298
Yu X, Yang Y, Yuan H et al (2017) Inhibition of COX-2/PGE2 cascade ameliorates cisplatin-induced mesangial cell apoptosis. Am J Transl Res 9(3):1222–1229
Zhang Y, Li Q, Rao E et al (2015) Epidermal Fatty Acid binding protein promotes skin inflammation induced by high-fat diet. Immunity 42:953–964
Zhang P, Yu J, Gui Y, Sun C, Han W (2019) Inhibition of miRNA-222-3p relieves staphylococcal enterotoxin B-induced liver inflammatory injury by upregulating suppressors of cytokine signaling 1. Yonsei Med J 60:1093–1102
Zhuang Y, Zhao F, Liang J et al (2017) Activation of COX-2/mPGES-1/PGE2 cascade via NLRP3 inflammasome contributes to albumin-induced proximal tubule cell injury. Cell Physiol Biochem 42(2):797–807
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No 81702408). The authors thank Pro Rui Liao (Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University) for some helpful advice in article revision.
Funding
This work was supported by the National Natural Science Foundation of China (No 81702408).
Author information
Authors and Affiliations
Contributions
LP: conceptualization, methodology, software, and writing—reviewing and editing YP: data curation and writing—original draft preparation. HX: visualization and investigation. XD: supervision, software, and validation. QC: investigation and software.
Corresponding author
Ethics declarations
Conflict of interest
Long Pan declares that he has no conflict of interest. Yihan Pang declares that she has no conflict of interest. Heng Xiao declares that he has no conflict of interest. Xin Deng declares that he has no conflict of interest. Qingsong Chen declares that he has no conflict of interest.
Ethical approval
All the authors declare that all the experimental procedures were performed in accordance with the ethical standards as recommended by the Institutional Committee of Review Board of the First Affiliated Hospital of Chongqing Medical University.
Informed consent
Informed consent was obtained from each patient.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Pan, L., Pang, Y., Xiao, H. et al. Fatty acid-binding protein 5 activates cyclooxygenase-2 and promotes hypoxic injury in LO2 cells. Mol. Cell. Toxicol. 18, 23–30 (2022). https://doi.org/10.1007/s13273-021-00158-1
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13273-021-00158-1