{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T13:46:19Z","timestamp":1787060779719,"version":"build-2736575974"},"reference-count":51,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T00:00:00Z","timestamp":1724716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>To elucidate the possible biological roles of fatty acid-binding protein 5 (FABP5) in the intraocular environment, the cells from which FABP5 originates were determined by using four different intraocular tissue-derived cell types including human non-pigmented ciliary epithelium (HNPCE) cells, retinoblastoma (RB) cells, adult retinal pigment epithelial19 (ARPE19) cells and human ocular choroidal fibroblast (HOCF) cell lines, and the effects of FABP ligand 6, a specific inhibitor for FABP5 and FABP7 were analyzed by RNA sequencing and seahorse cellular metabolic measurements. Among these four different cell types, qPCR analysis showed that FABP5 was most prominently expressed in HNPCE cells, in which no mRNA expression of FABP7 was detected. In RNA sequencing analysis, 166 markedly up-regulated and 198 markedly down-regulated differentially expressed genes (DEGs) were detected between non-treated cells and cells treated with FABP ligand 6. IPA analysis of these DEGs suggested that FABP5 may be involved in essential roles required for cell development, cell survival and cell homeostasis. In support of this possibility, both mitochondrial and glycolytic functions of HNPCE cells, in which mRNA expression of FABP5, but not that of FABP7, was detected, were shown by using a Seahorse XFe96 Bioanalyzer to be dramatically suppressed by FABP ligand 6-induced inhibition of the activity of FABP5. Furthermore, in IPA upstream analysis, various unfolded protein response (UPR)-related factors were identified as upstream and causal network master regulators. Analysis by qPCR analysis showed significant upregulation of the mRNA expression of most of UPR-related factors and aquaporin1 (AQP1). The findings in this study suggest that HNPCE is one of intraocular cells producing FABP5 and may be involved in the maintenance of UPR and AQP1-related functions of HNPCE.<\/jats:p>","DOI":"10.3390\/ijms25179285","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T09:26:51Z","timestamp":1724750811000},"page":"9285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["FABP5 Is a Possible Factor for the Maintenance of Functions of Human Non-Pigmented Ciliary Epithelium Cells"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0534-0257","authenticated-orcid":false,"given":"Megumi","family":"Higashide","sequence":"first","affiliation":[{"name":"Departments of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8026-6532","authenticated-orcid":false,"given":"Megumi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7876-1772","authenticated-orcid":false,"given":"Tatsuya","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan"},{"name":"Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Araya","family":"Umetsu","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9894-8523","authenticated-orcid":false,"given":"Nami","family":"Nishikiori","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshifumi","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan"},{"name":"Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0145-3541","authenticated-orcid":false,"given":"Masato","family":"Furuhashi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Ohguro","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/nrd2589","article-title":"Fatty acid-binding proteins: Role in metabolic diseases and potential as drug targets","volume":"7","author":"Furuhashi","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/nrendo.2015.122","article-title":"Metabolic functions of FABPs--mechanisms and therapeutic implications","volume":"11","author":"Hotamisligil","year":"2015","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"216","DOI":"10.5551\/jat.48710","article-title":"Fatty Acid-Binding Protein 4 in Cardiovascular and Metabolic Diseases","volume":"26","author":"Furuhashi","year":"2019","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1194\/jlr.M800102-JLR200","article-title":"Plasma fatty acid binding protein 4 is associated with atherogenic dyslipidemia in diabetes","volume":"49","author":"Girona","year":"2008","journal-title":"J. Lipid. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3657","DOI":"10.2174\/0929867325666181008154622","article-title":"Role of Fatty Acid Binding Protein 4 (FABP4) in Kidney Disease","volume":"27","author":"Shi","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"R173","DOI":"10.1530\/JOE-17-0031","article-title":"Role of the fatty acid-binding protein 4 in heart failure and cardiovascular disease","volume":"233","author":"Girona","year":"2017","journal-title":"J. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sun, N., and Zhao, X. (2022). Therapeutic Implications of FABP4 in Cancer: An Emerging Target to Tackle Cancer. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.948610"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e1221","DOI":"10.1016\/S2214-109X(17)30393-5","article-title":"Global causes of blindness and distance vision impairment 1990\u20132020: A systematic review and meta-analysis","volume":"5","author":"Flaxman","year":"2017","journal-title":"Lancet Glob. Health"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/S0140-6736(09)62124-3","article-title":"Diabetic retinopathy","volume":"376","author":"Cheung","year":"2010","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"010427","DOI":"10.7189\/jogh.09.010427","article-title":"Global epidemiology of retinal vein occlusion: A systematic review and meta-analysis of prevalence, incidence, and risk factors","volume":"9","author":"Song","year":"2019","journal-title":"J. Glob. Health"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.ophtha.2009.07.017","article-title":"The prevalence of retinal vein occlusion: Pooled data from population studies from the United States, Europe, Asia, and Australia","volume":"117","author":"Rogers","year":"2010","journal-title":"Ophthalmology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"102473","DOI":"10.1016\/j.plefa.2022.102473","article-title":"Fatty acid metabolism is involved in both retinal physiology and the pathology of retinal vascular diseases","volume":"183","author":"Umetsu","year":"2022","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ohguro, H., Watanabe, M., Sato, T., Nishikiori, N., Umetsu, A., Higashide, M., Ogawa, T., and Furuhashi, M. (2024). FABP4 Is an Indispensable Factor for Regulating Cellular Metabolic Functions of the Human Retinal Choroid. Bioengineering, 11.","DOI":"10.3390\/bioengineering11060584"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.preteyeres.2012.10.004","article-title":"A contemporary concept of the blood-aqueous barrier","volume":"32","author":"Freddo","year":"2013","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S1569-2590(05)10005-6","article-title":"Ciliary Body and Ciliary Epithelium","volume":"10","author":"Delamere","year":"2005","journal-title":"Adv. Organ Biol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Marrero, I., Hern\u00e1ndez-Abad, L.G., Carmona-Calero, E.M., Casta\u00f1eyra-Ruiz, L., Abreu-Reyes, J.A., and Casta\u00f1eyra-Perdomo, A. (2018). Systemic Hypertension Effects on the Ciliary Body and Iris. An Immunofluorescence Study with Aquaporin 1, Aquaporin 4, and Na\u207a, K\u207a ATPase in Hypertensive Rats. Cells, 7.","DOI":"10.3390\/cells7110210"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1177\/11206721211031409","article-title":"Diagnostic imaging of the ciliary body: Technologies, outcomes, and future perspectives","volume":"32","author":"Kudsieh","year":"2022","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_18","first-page":"958","article-title":"Intercellular junctions in the ciliary epithelium","volume":"17","author":"Raviola","year":"1978","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3109\/02713689209000061","article-title":"Expression and cellular distribution of the alpha 1 gap junction gene product in the ocular pigmented ciliary epithelium","volume":"11","author":"Ghosh","year":"1992","journal-title":"Curr. Eye Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1002\/jcp.1041490203","article-title":"Expression of multiple Na+,K(+)-ATPase genes reveals a gradient of isoforms along the nonpigmented ciliary epithelium: Functional implications in aqueous humor secretion","volume":"149","author":"Ghosh","year":"1991","journal-title":"J. Cell. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1006\/exer.1993.1083","article-title":"Differential expression of the cellular retinaldehyde-binding protein in bovine ciliary epithelium","volume":"56","author":"Ghosh","year":"1993","journal-title":"Exp. Eye Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/0014-4835(92)90175-R","article-title":"Isolation of a cDNA encoding a glutathione S-transferase (GST) class-pi from the bovine ocular ciliary epithelium","volume":"55","author":"Hernando","year":"1992","journal-title":"Exp. Eye Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"169","DOI":"10.3109\/02713688109001822","article-title":"Circadian rhythm in intraocular pressure: A rabbit model","volume":"1","author":"Rowland","year":"1981","journal-title":"Curr. Eye Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S1350-9462(98)00014-7","article-title":"Neuronal death in glaucoma","volume":"18","author":"Quigley","year":"1999","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1093\/oxfordjournals.jbchem.a124168","article-title":"Cloning of the bovine plasma selenium-dependent glutathione peroxidase (GP) cDNA from the ocular ciliary epithelium: Expression of the plasma and cellular forms within the mammalian eye","volume":"114","author":"Ghosh","year":"1993","journal-title":"J. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1046\/j.1471-4159.1996.66020787.x","article-title":"Identification of a neuropeptide and neuropeptide-processing enzymes in aqueous humor confers neuroendocrine features to the human ocular ciliary epithelium","volume":"66","author":"Ortego","year":"1996","journal-title":"J. Neurochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S1350-9462(98)00026-3","article-title":"Differential gene expression in the human ciliary epithelium","volume":"18","author":"Escribano","year":"1999","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_28","first-page":"443","article-title":"Fatty acid-binding protein from embryonic chick retina resembles mammalian heart fatty acid-binding protein","volume":"35","author":"Sellner","year":"1994","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1038\/sj.onc.1206341","article-title":"High-level expression of cutaneous fatty acid-binding protein in prostatic carcinomas and its effect on tumorigenicity","volume":"22","author":"Adamson","year":"2003","journal-title":"Oncogene"},{"key":"ref_30","first-page":"4357","article-title":"Human cutaneous fatty acid-binding protein induces metastasis by up-regulating the expression of vascular endothelial growth factor gene in rat Rama 37 model cells","volume":"61","author":"Jing","year":"2001","journal-title":"Cancer Res."},{"key":"ref_31","first-page":"767","article-title":"Expression of cutaneous fatty acid-binding protein (C-FABP) in prostate cancer: Potential prognostic marker and target for tumourigenicity-suppression","volume":"32","author":"Morgan","year":"2008","journal-title":"Int. J. Oncol."},{"key":"ref_32","first-page":"69","article-title":"Atelocollagen-delivered siRNA targeting the FABP5 gene as an experimental therapy for prostate cancer in mouse xenografts","volume":"36","author":"Forootan","year":"2010","journal-title":"Int. J. Oncol."},{"key":"ref_33","first-page":"e21395","article-title":"NUPR1 protects liver from lipotoxic injury by improving the endoplasmic reticulum stress response","volume":"35","author":"Listi","year":"2021","journal-title":"Faseb. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"533","DOI":"10.2174\/1566524016666160523143937","article-title":"The Role of the PERK\/eIF2\u03b1\/ATF4\/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress","volume":"16","author":"Rozpedek","year":"2016","journal-title":"Curr. Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3373","DOI":"10.1080\/15384101.2015.1090066","article-title":"p53-mediated control of gene expression via mRNA translation during Endoplasmic Reticulum stress","volume":"14","author":"Tournillon","year":"2015","journal-title":"Cell Cycle (Georget. Tex.)"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"112986","DOI":"10.1016\/j.celrep.2023.112986","article-title":"FoxM1 coordinates cell division, protein synthesis, and mitochondrial activity in a subset of \u03b2 cells during acute metabolic stress","volume":"42","author":"Kobiita","year":"2023","journal-title":"Cell Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"154577","DOI":"10.1016\/j.cyto.2018.10.018","article-title":"Crosstalk between inflammatory mediators and endoplasmic reticulum stress in liver diseases","volume":"124","author":"Duvigneau","year":"2019","journal-title":"Cytokine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1093\/humrep\/deaa077","article-title":"Metformin inhibits testosterone-induced endoplasmic reticulum stress in ovarian granulosa cells via inactivation of p38 MAPK","volume":"35","author":"Jin","year":"2020","journal-title":"Hum. Reprod. (Oxf. Engl.)"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"40576","DOI":"10.1074\/jbc.M006524200","article-title":"The AROM gene, spliced mRNAs encoding new DNA\/RNA-binding proteins are transcribed from the opposite strand of the melanin-concentrating hormone gene in mammals","volume":"275","author":"Borsu","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Furuhashi, M., Sakuma, I., Morimoto, T., Higashiura, Y., Sakai, A., Matsumoto, M., Sakuma, M., Shimabukuro, M., Nomiyama, T., and Arasaki, O. (2020). Independent and Distinct Associations of FABP4 and FABP5 with Metabolic Parameters in Type 2 Diabetes Mellitus. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.575557"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Higashide, M., Furuhashi, M., Watanabe, M., Itoh, K., Suzuki, S., Umetsu, A., Tsugeno, Y., Ida, Y., Hikage, F., and Ohguro, H. (2022). Fatty Acid-Binding Proteins 4 and 5 Are Involved in the Pathogenesis of Retinal Vascular Diseases in Different Manners. Life, 12.","DOI":"10.3390\/life12040467"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Umetsu, A., Tanaka, M., Sato, T., Akiyama, Y., Endo, K., Mori, K., Ohnishi, H., Watanabe, M., Ohguro, H., and Hanawa, N. (2024). High Intraocular Pressure Is Independently Associated with New-Onset Systemic Hypertension over a 10-Year Period. Circ. J.","DOI":"10.1253\/circj.CJ-24-0241"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1038\/nm.2067","article-title":"Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis","volume":"15","author":"Erbay","year":"2009","journal-title":"Nat. Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Watanabe, M., Sato, T., Tsugeno, Y., Higashide, M., Furuhashi, M., and Ohguro, H. (2023). TGF-\u03b2-3 Induces Different Effects from TGF-\u03b2-1 and -2 on Cellular Metabolism and the Spatial Properties of the Human Trabecular Meshwork Cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24044181"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Ichioka, H., Hirohashi, Y., Sato, T., Furuhashi, M., Watanabe, M., Ida, Y., Hikage, F., Torigoe, T., and Ohguro, H. (2023). G-Protein-Coupled Receptors Mediate Modulations of Cell Viability and Drug Sensitivity by Aberrantly Expressed Recoverin 3 within A549 Cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010771"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: A fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_47","first-page":"523","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Green","year":"2014","journal-title":"Bioinform. (Oxf. Engl.)"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.3892\/ijmm.2020.4661","article-title":"Ingenuity pathway analysis of differentially expressed genes involved in signaling pathways and molecular networks in RhoE gene-edited cardiomyocytes","volume":"46","author":"Shao","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Alimadadi, A., Aryal, S., Manandhar, I., Joe, B., and Cheng, X. (2020). Identification of Upstream Transcriptional Regulators of Ischemic Cardiomyopathy Using Cardiac RNA-Seq Meta-Analysis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103472"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Ida, Y., Hikage, F., Itoh, K., Ida, H., and Ohguro, H. (2020). Prostaglandin F2\u03b1 agonist-induced suppression of 3T3-L1 cell adipogenesis affects spatial formation of extra-cellular matrix. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-64674-1"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1167\/iovs.61.6.13","article-title":"Prostaglandin F2\u03b1 Agonists Negatively Modulate the Size of 3D Organoids from Primary Human Orbital Fibroblasts","volume":"61","author":"Itoh","year":"2020","journal-title":"Investig. Ophthalmol. Vis. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/17\/9285\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:43:32Z","timestamp":1760111012000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/17\/9285"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,27]]},"references-count":51,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms25179285"],"URL":"https:\/\/doi.org\/10.3390\/ijms25179285","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,27]]}}}