miRNA-mRNA profile and regulatory network in stearic acid-treated β-cell dysfunction

in Journal of Endocrinology

Correspondence should be addressed to H Lu or C Sun: lhm_519@sina.com or changhaosun2002@163.com
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Chronic exposure of pancreatic β-cells to saturated fatty acid (palmitic or stearic acid) is a leading cause of impaired insulin secretion. However, the molecular mechanisms underlying stearic-acid-induced β-cell dysfunction remain poorly understood. Emerging evidence indicates that miRNAs are involved in various biological functions. The aim of this study was to explore the differential expression of miRNAs and mRNAs, specifically in stearic-acid-treated- relative to palmitic-acid-treated β-cells, and to establish their co-expression networks. β-TC-6 cells were treated with stearic acid, palmitic acid or normal medium for 24 h. Differentially expressed miRNAs and mRNAs were identified by high-throughput sequencing and bioinformatic analysis. Co-expression network, gene ontology (GO) and pathway analyses were then conducted. Changes in the expression of selected miRNAs and mRNAs were verified in β-TC-6 cells and mouse islets. Sequencing analysis detected 656 known and 1729 novel miRNAs. miRNA-mRNA network and Venn-diagram analysis yielded two differentially expressed miRNAs and 63 mRNAs exclusively in the stearic-acid group. miR-374c-5p was up-regulated by a 1.801 log2(fold-change) and miR-297b-5p was down-regulated by a −4.669 log2(fold-change). We found that miR-297b-5p and miR-374c-5p were involved in stearic-acid-induced lipotoxicity to β-TC-6 cells. Moreover, the effects of miR-297b-5p and miR-374c-5p on the alterations of candidate mRNAs expressions were verified. This study indicates that expression changes of specific miRNAs and mRNAs may contribute to stearic-acid-induced β-cell dysfunction, which provides a preliminary basis for further functional and molecular mechanism studies of stearic-acid-induced β-cell dysfunction in the development of type 2 diabetes.

Supplementary Materials

    • Supplementary Table 1 The composition of the diet for mice
    • Supplementary Table 2 The differentially expressed miRNA in palmitic acid-induced β-TC 6 cells compared both with stearic acid and control group.
    • Supplementary Table 3 The differentially expressed miRNAs both in stearic and palmitic acid-induced β-TC 6 cells compared with control group.
    • Supplementary Table 4 The log2FoldChange of differentially expressed mRNAs in stearic acid-induced β-TC 6 cells compared both with palmitic acid and control group.
    • Supplementary Table 5 The log2FoldChange of differentially expressed mRNAs in palmitic acid-induced β-TC 6 cells compared both with stearic acid and control group.
    • Supplementary Table 6 The top 10 up- and down-regulated differentially expressed mRNAs both in stearic and palmitic acid-induced β-TC 6 cells compared with control group.
    • Supplementary Table 7 The composition of fasting serum NEFAs profile in normal and HSD mice at 16 weeks
    • Supplementary Table 8 Body weight and serum analysis in normal and HSD mice at 16 weeks.

 

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  • Acosta-MontañoPGarcía-GonzálezV 2018 Effects of dietary fatty acids in pancreatic beta cell metabolism, implications in homeostasis. Nutrients 10 393. (https://doi.org/10.3390/nu10040393)

    • Search Google Scholar
    • Export Citation
  • Acosta-MontañoPRodríguez-VelázquezEIbarra-LópezEFrayde-GómezHMas-OlivaJDelgado-CoelloBRiveroIAAlatorre-MedaMAguileraJGuevara-OlayaLet al. 2019 Fatty acid and lipopolysaccharide effect on beta cells proteostasis and its impact on insulin secretion. Cells 8 884. (https://doi.org/10.3390/cells8080884)

    • Search Google Scholar
    • Export Citation
  • AmbrosV 2004 The functions of animal microRNAs. Nature 431 350355. (https://doi.org/10.1038/nature02871)

  • BartelDP 2018 Metazoan microRNAs. Cell 173 2051. (https://doi.org/10.1016/j.cell.2018.03.006)

  • BelgardtBFAhmedKSprangerMLatreilleMDenzlerRKondratiukNvon MeyennFVillenaFNHerrmannsKBoscoDet al. 2015 The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes. Nature Medicine 21 619627. (https://doi.org/10.1038/nm.3862)

    • Search Google Scholar
    • Export Citation
  • ChenCCohrsCMStertmannJBozsakRSpeierS 2017 Human beta cell mass and function in diabetes: recent advances in knowledge and technologies to understand disease pathogenesis. Molecular Metabolism 6 943957. (https://doi.org/10.1016/j.molmet.2017.06.019)

    • Search Google Scholar
    • Export Citation
  • ChuXLiuLNaLLuHLiSLiYSunC 2013 Sterol regulatory element-binding protein-1c mediates increase of postprandial stearic acid, a potential target for improving insulin resistance, in hyperlipidemia. Diabetes 62 561571. (https://doi.org/10.2337/db12-0139)

    • Search Google Scholar
    • Export Citation
  • DhayalSZummoFPAndersonMWThomasPWeltersHJArdenCMorganNG 2019 Differential effects of saturated and unsaturated fatty acids on autophagy in pancreatic β-cells. Journal of Molecular Endocrinology 63 285296. (https://doi.org/10.1530/JME-19-0096)

    • Search Google Scholar
    • Export Citation
  • ElsnerMGehrmannWLenzenS 2011 Peroxisome-generated hydrogen peroxide as important mediator of lipotoxicity in insulin-producing cells. Diabetes 60 200208. (https://doi.org/10.2337/db09-1401)

    • Search Google Scholar
    • Export Citation
  • FlyntASLaiEC 2008 Biological principles of microRNA-mediated regulation: shared themes amid diversity. Nature Reviews: Genetics 9 831842. (https://doi.org/10.1038/nrg2455)

    • Search Google Scholar
    • Export Citation
  • FürstovaVKopskaTJamesRFLKovarJ 2008 Comparison of the effect of individual saturated and unsaturated fatty acids on cell growth and death induction in the human pancreatic β-cell line NES2Y. Life Sciences 82 684691. (https://doi.org/10.1016/j.lfs.2007.12.023)

    • Search Google Scholar
    • Export Citation
  • GBD 2015 Disease and Injury Incidence and Prevalence Collaborators 2016 Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388 15451602. (https://doi.org/10.1016/S0140-6736(16)31678-6)

    • Search Google Scholar
    • Export Citation
  • GehrmannWElsnerMLenzenS 2010 Role of metabolically generated reactive oxygen species for lipotoxicity in pancreatic β-cells. Diabetes Obesity and Metabolism 12 149158. (https://doi.org/10.1111/j.1463-1326.2010.01265.x)

    • Search Google Scholar
    • Export Citation
  • GiaccaAXiaoCOprescuAICarpentierACLewisGF 2011 Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies. American Journal of Physiology: Endocrinology and Metabolism 300 E255E262. (https://doi.org/10.1152/ajpendo.00416.2010)

    • Search Google Scholar
    • Export Citation
  • GoldsteinJLBasuSKBrownMS 1983 Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. In Methods in Enzymology pp. 241260. Cambridge MA USA: Academic Press. (https://doi.org/10.1016/0076-6879(83)98152-1)

    • Search Google Scholar
    • Export Citation
  • GuayCRegazziR 2015 MicroRNAs and the functional β cell mass: for better or worse. Diabetes and Metabolism 41 369377. (https://doi.org/10.1016/j.diabet.2015.03.006)

    • Search Google Scholar
    • Export Citation
  • GuoRYuYZhangYLiYChuXLuHSunC 2020 Overexpression of miR-297b-5p protects against stearic acid-induced pancreatic β-cell apoptosis by targeting LATS2. American Journal of Physiology: Endocrinology and Metabolism 318 E430E439. (https://doi.org/10.1152/ajpendo.00302.2019)

    • Search Google Scholar
    • Export Citation
  • JiangQWangYHaoYJuanLTengMZhangXLiMWangGLiuY 2009 miR2Disease: a manually curated database for microRNA deregulation in human disease. Nucleic Acids Research 37 D98D104. (https://doi.org/10.1093/nar/gkn714)

    • Search Google Scholar
    • Export Citation
  • LiXGLiLZhouXChenYRenYPZhouTYLuW 2012 Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats. Acta Pharmacologica Sinica 33 13791386. (https://doi.org/10.1038/aps.2012.33)

    • Search Google Scholar
    • Export Citation
  • ListenbergerLLHanXLewisSECasesSFareseRVJrOryDSSchafferJE 2003 Triglyceride accumulation protects against fatty acid-induced lipotoxicity. PNAS 100 30773082. (https://doi.org/10.1073/pnas.0630588100)

    • Search Google Scholar
    • Export Citation
  • LuHHaoLLiSLinSLvLChenYCuiHZiTChuXNaLet al. 2016a Elevated circulating stearic acid leads to a major lipotoxic effect on mouse pancreatic beta cells in hyperlipidaemia via a miR-34a-5p-mediated PERK/p53-dependent pathway. Diabetologia 59 12471257. (https://doi.org/10.1007/s00125-016-3900-0)

    • Search Google Scholar
    • Export Citation
  • LuYWangYOngCNSubramaniamTChoiHWYuanJMKohWPPanA 2016b Metabolic signatures and risk of type 2 diabetes in a Chinese population: an untargeted metabolomics study using both LC-MS and GC-MS. Diabetologia 59 23492359. (https://doi.org/10.1007/s00125-016-4069-2)

    • Search Google Scholar
    • Export Citation
  • LuYWangYZouLLiangXOngCNTavintharanSYuanJMKohWPPanA 2018 Serum lipids in association with Type 2 diabetes risk and prevalence in a Chinese population. Journal of Clinical Endocrinology and Metabolism 103 671680. (https://doi.org/10.1210/jc.2017-02176)

    • Search Google Scholar
    • Export Citation
  • MarafieSKAl-ShawafEMAbubakerJArefanianH 2019 Palmitic acid-induced lipotoxicity promotes a novel interplay between Akt-mTOR, IRS-1, and FFAR1 signaling in pancreatic β-cells. Biological Research 52 44. (https://doi.org/10.1186/s40659-019-0253-4)

    • Search Google Scholar
    • Export Citation
  • MorganNGDhayalS 2010 Unsaturated fatty acids as cytoprotective agents in the pancreatic beta-cell. Prostaglandins Leukotrienes and Essential Fatty Acids 82 231236. (https://doi.org/10.1016/j.plefa.2010.02.018)

    • Search Google Scholar
    • Export Citation
  • NemeczMConstantinADumitrescuMAlexandruNFilippiATankoGGeorgescuA 2019 The distinct effects of palmitic and oleic acid on pancreatic beta cell function: the elucidation of associated mechanisms and effector molecules. Frontiers in Pharmacology 9 1554. (https://doi.org/10.3389/fphar.2018.01554)

    • Search Google Scholar
    • Export Citation
  • ÖzcanS 2015 MicroRNAs in pancreatic β-cell physiology. In MicroRNA: Basic Science: From Molecular Biology to Clinical Practice pp. 101117. Ed SantulliG. Cham, Switzerland: Springer International Publishing. (https://doi.org/10.1007/978-3-319-22380-3_6)

    • Search Google Scholar
    • Export Citation
  • PlaisanceVWaeberGRegazziRAbderrahmaniA 2014 Role of microRNAs in islet beta-cell compensation and failure during diabetes. Journal of Diabetes Research 2014 618652. (https://doi.org/10.1155/2014/618652)

    • Search Google Scholar
    • Export Citation
  • PordzikJJakubikDJarosz-PopekJWicikZEyiletenCDe RosaSIndolfiCSiller-MatulaJMCzajkaPPostulaM 2019 Significance of circulating microRNAs in diabetes mellitus type 2 and platelet reactivity: bioinformatic analysis and review. Cardiovascular Diabetology 18 113. (https://doi.org/10.1186/s12933-019-0918-x)

    • Search Google Scholar
    • Export Citation
  • RisérusUWillettWCHuFB 2009 Dietary fats and prevention of type 2 diabetes. Progress in Lipid Research 48 4451. (https://doi.org/10.1016/j.plipres.2008.10.002)

    • Search Google Scholar
    • Export Citation
  • RoompKKristinssonHSchvartzDUbhayasekeraKSargsyanEManukyanLChowdhuryAManellHSatagopamVGroebeKet al. 2017 Combined lipidomic and proteomic analysis of isolated human islets exposed to palmitate reveals time-dependent changes in insulin secretion and lipid metabolism. PLoS ONE 12 e0176391. (https://doi.org/10.1371/journal.pone.0176391)

    • Search Google Scholar
    • Export Citation
  • SmythSHeronA 2006 Diabetes and obesity: the twin epidemics. Nature Medicine 12 7580. (https://doi.org/10.1038/nm0106-75)

  • SongYJinDJiangXLvCZhuH 2018 Overexpression of microRNA-26a protects against deficient β-cell function via targeting phosphatase with tensin homology in mouse models of type 2 diabetes. Biochemical and Biophysical Research Communications 495 13121316. (https://doi.org/10.1016/j.bbrc.2017.11.170)

    • Search Google Scholar
    • Export Citation
  • ŠrámekJNěmcová-FürstováVPavlíkováNKovářJ 2017 Effect of saturated stearic acid on MAP kinase and ER stress signaling pathways during apoptosis induction in human pancreatic β-cells is inhibited by unsaturated oleic acid. International Journal of Molecular Sciences 18 2313. (https://doi.org/10.3390/ijms18112313)

    • Search Google Scholar
    • Export Citation
  • SuttonRPetersMMcShanePGrayDWRMorrisPJ 1986 Isolation of rat pancreatic islets by ductal injection of collagenase. Transplantation 42 689690. (https://doi.org/10.1097/00007890-198612000-00022)

    • Search Google Scholar
    • Export Citation
  • TholstrupTHjerpstedJRaffM 2011 Palm olein increases plasma cholesterol moderately compared with olive oil in healthy individuals. American Journal of Clinical Nutrition 94 14261432. (https://doi.org/10.3945/ajcn.111.018846)

    • Search Google Scholar
    • Export Citation
  • van den BergSAGuigasBBijlandSOuwensMVosholPJFrantsRRHavekesLMRomijnJAvan DijkKW 2010 High levels of dietary stearate promote adiposity and deteriorate hepatic insulin sensitivity. Nutrition and Metabolism 7 24. (https://doi.org/10.1186/1743-7075-7-24)

    • Search Google Scholar
    • Export Citation
  • WelshNCnopMKharroubiIBuglianiMLupiRMarchettiPEizirikDL 2005 Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets? Diabetes 54 (Supplement 97) 32383244. (https://doi.org/10.2337/diabetes.54.11.3238)

    • Search Google Scholar
    • Export Citation
  • ZhuHLeungSW 2015 Identification of microRNA biomarkers in type 2 diabetes: a meta-analysis of controlled profiling studies. Diabetologia 58 900911. (https://doi.org/10.1007/s00125-015-3510-2)

    • Search Google Scholar
    • Export Citation