Insulin resistance in obese adolescents affects the expression of genes associated with immune response

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Objective. The development of obesity and its metabolic complications is associated with dysregulation of various intrinsic mechanisms, which control basic metabolic processes through changes in the expression of numerous regulatory genes.

Methods. The expression level of HLA-DRA, HLA-DRB1, HLA-G, HLA-F, and NFX1 genes as well as miR-190b was measured in the blood of obese adolescents without signs of resistance to insulin and with insulin resistance in comparison with the group of relative healthy control individuals without signs of obesity.

Results. It was shown that obesity without signs of insulin resistance is associated with upregulation of the expression level of HLA-DRA and HLA-DRB1 genes, but with down-regulation of HLA-G gene expression in the blood as compared to control group of relative healthy adolescents. At the same time, no significant changes were observed in the expression level of HLA-F and NFX1 genes in the blood of this group of obese adolescents. Development of insulin resistance in obese individuals leads to significant down-regulation of HLA-DRA, HLA-DRB1, HLA-G, and HLA-F gene expressions as well as to up-regulation of NFX1 gene as well as microRNA miR-190b in the blood as compared to obese patients without signs of insulin resistance.

Conclusions. Results of this study provide evidence that obesity affects the expression of the subset of genes related to immune response in the blood and that development of insulin resistance in obese adolescents is associated with strong down-regulation of the expressions of HLA-DRA, HLA-DRB1, HLA-F, and HLA-G genes, which may be contribute to the development of obesity complications. It is possible that transcription factor NFX1 and miR-190b participate in downregulation of HLA-DRA gene expression in the blood of obese adolescents with insulin resistance.

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  • Amiot L Vu N Samson M. Biology of the immunomodulatory molecule HLA-G in human liver diseases. J Hepatol 62 1430–1437 2015.

  • Ando H Kumazaki M Motosugi Y Ushijima K Maekawa T Ishikawa E Fujimura A. Impairment of peripheral circadian clocks precedes metabolic abnormalities in ob/ob mice. Endocrinology 152 1347–1354 2011.

  • Auf G Jabouille A Delugin M Guerit S Pineau R North S Platonova N Maitre M Favereaux A Vajkoczy P Seno M Bikfalvi A Minchenko D Minchenko O Moenner M. High epiregulin expression in human U87 glioma cells relies on IRE1 alpha and promotes autocrine growth through EGF receptor. BMC Cancer 13 597 2013.

  • Bass R Eneli I. Severe childhood obesity: an under-recognised and growing health problem. Postgrad Med J 91 639–645 2015.

  • Bochkov VN Philippova M Oskolkova O Kadl A Furnkranz A Karabeg E Breuss J Minchenko OH Mechtcheriakova D Hohensinner P Rychli K Wojta J Resink T Binder BR Leitinger N. Oxidized phospholipids stimulate angiogenesis via induction of VEGF IL-8 COX-2 and ADAMTS-1 metalloprotease implicating a novel role for lipid oxidation in progression and destabilization of atherosclerotic lesions. Circ Res 99 900–908 2006.

  • Boegel S Lower M Bukur T Sorn P Castle JC Sahin U. HLA and proteasome expression body map. BMC Med Genomics 11 36 2018.

  • Brown PJ Wong KK Felce SL Lyne L Spearman H Soilleux EJ Pedersen LM Moller MB Green TM Gascoyne DM Banham AH. FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas. Leukemia 30 605–616 2016.

  • Cajander S Backman A Tina E Stralin K Soderquist B Kallman J. Preliminary results in quantitation of HLA-DRA by real-time PCR: a promising approach to identify immunosuppression in sepsis. Crit Care 17 R223 2013.

  • Cajander S Tina E Backman A Magnuson A Stralin K Soderquist B Kallman J. Quantitative real-time polymerase chain reaction measurement of HLA-DRA gene expression in whole blood is highly reproducible and shows changes that reflect dynamic shifts in monocyte surface HLA-DR expression during the course of sepsis. PLoS One 11 e0154690 2016.

  • Carosella ED Rouas-Freiss N Tronik-Le Roux D Moreau P LeMaoult J. HLA-G: an immune checkpoint molecule. Adv Immunol 127 33–144 2015.

  • Chevet E Hetz C Samali A. Endoplasmic reticulum stress-activated cell reprogramming in oncogenesis. Cancer Discov 5 586–597 2015.

  • Cizeron-Clairac G Lallemand F Vacher S Lidereau R Bieche I Callens C. MiR-190b the highest up-regulated miRNA in ERalpha-positive compared to ERalpha-negative breast tumors a new biomarker in breast cancers? BMC Cancer 15 499 2015.

  • Doultsinos D Avril T Lhomond S Dejeans N Guedat P Chevet E. Control of the unfolded protein response in health and disease. SLAS Discov 22 787–800 2017.

  • Farjadian S Tabebordbar M Mokhtari M Safaei A Malekzadeh M Ghaderi A. HLA-G expression in tumor tissues and soluble HLA-G plasma levels in patients with gastrointestinal cancer. Asian Pac J Cancer Prev 19 2731–2735 2018.

  • Han J Kaufman RJ. Measurement of the unfolded protein response to investigate its role in adipogenesis and obesity. Methods Enzymol 538 135–150 2014.

  • Harada A Ishigami S Kijima Y Nakajo A Arigami T Kurahara H Kita Y Yoshinaka H Natsugoe S. Clinical implication of human leukocyte antigen (HLA)-F expression in breast cancer. Pathol Int 65 569–574 2015.

  • Hassler JR Scheuner DL Wang S Han J Kodali VK Li P Nguyen J George JS Davis C Wu SP Bai Y Sartor M Cavalcoli J Malhi H Baudouin G Zhang Y Yates Iii JR Itkin-Ansari P Volkmann N Kaufman RJ. The IRE1α/ XBP1s pathway is essential for the glucose response and protection of β cells. PLoS Biol 13 e1002277 2015.

  • Ishigami S Arigami T Okumura H Uchikado Y Kita Y Kurahara H Maemura K Kijima Y Ishihara Y Sasaki K Uenosono Y Natsugoe S. Human leukocyte antigen (HLA)-E and HLA-F expression in gastric cancer. Anticancer Res 35 2279–2285 2015.

  • Ishitani A Geraghty DE. Alternative splicing of HLA-G transcripts yields proteins with primary structures resembling both class I and class II antigens. Proc Natl Acad Sci USA 89 3947–3951 1992.

  • Kochan G Escors D Breckpot K Guerrero-Setas D. Role of non-classical MHC class I molecules in cancer immunosuppression. Oncoimmunology 2 e26491 2013.

  • Lee J Ozcan U. Unfolded protein response signaling and metabolic diseases. J Biol Chem 289 1203–1211 2014.

  • Leite FA Lira RC Fedatto PF Antonini SR Martinelli CE Jr de Castro M Neder L Ramalho LN Tucci S Jr Mastelaro MJ Seidinger AL Cardinalli IA Yunes JA Brandalise SR Tone LG Scrideli CA. Low expression of HLA-DRA HLA-DPA1 and HLA-DPB1 is associated with poor prognosis in pediatric adrenocortical tumors (ACT). Pediatr Blood Cancer 61 1940–1948 2014.

  • Li P Noegel AA. Inner nuclear envelope protein SUN1 plays a prominent role in mammalian mRNA export. Nucleic Acids Res 43 9874–9888 2015.

  • Mao Z Zhang W. Role of mTOR in glucose and lipid metabolism. Int J Mol Sci 19 pii: E2043 2018.

  • Martinez-Canales S Cifuentes F Lopez De Rodas Gregorio M Serrano-Oviedo L Galan-Moya EM Amir E Pandiella A Gyorffy B Ocana A. Transcriptomic immunologic signature associated with favorable clinical outcome in basal-like breast tumors. PLoS One 12 e0175128 2017.

  • Marzuillo P Bellini G Punzo F Di Sessa A Guarino S Umano GR Toraldo R Miraglia Del Giudice E Rossi F. Association between 14 bp insertion/deletion HLA-G functional polymorphism and insulin resistance in a cohort of Italian children with obesity. Pediatr Diabetes 19 1357–1361 2018.

  • Minchenko DO Kharkova AP Hubenia OV Minchenko OH. Insulin receptor IRS1 IRS2 INSIG1 INSIG2 RRAD and BAIAP2 gene expressions in glioma U87 cells with ERN1 loss of function: effect of hypoxia and glutamine or glucose deprivation. Endocr Regul 47 15–26 2013.

  • Minchenko DO Kharkova AP Karbovskyi LL Minchenko OH. Expression of insulin-like growth factor binding protein genes and its hypoxic regulation in U87 glioma cells depends on ERN1 mediated signaling pathway of endoplasmic reticulum stress. Endocr Regul 49 73–83 2015a.

  • Minchenko DO Kharkova AP Halkin OV Karbovskyi LL Minchenko OH. Effect of hypoxia on the expression of genes encoded insulin-like growth factors and some related proteins in U87 glioma cells without IRE1 function. Endocr Regul 50 43–54 2016a.

  • Minchenko DO Riabovol OO Tsymbal DO Ratushna OO Minchenko OH. Inhibition of IRE1 affects the expression of genes encoded glucocorticoid receptor and some related factors and their hypoxic regulation in U87 glioma cells. Endocr Regul 50 127–136 2016b.

  • Mincenko DO Riabovol OO Ratushna OO Minchenko OH. Hypoxic regulation of the expression of genes encoded estrogen related proteins in U87 glioma cells: effect of IRE1 inhibition. Endocr Regul 51 8–19 2017.

  • Minchenko OH Opentanova IL Minchenko DO Ogura T Esumi H. Hypoxia induces transcription of 6-phosphofructo-2-kinase/fructose-26-bisphosphatase 4 gene via hypoxia-inducible factor-1alpha activation. FEBS Lett 576 14–20 2004.

  • Minchenko OH Ochiai A Opentanova IL Ogura T Minchenko DO Caro J Komisarenko SV Esumi H. Overexpression of 6-phosphofructo-2-kinase/fructose-26bisphosphatase-4 in the human breast and colon malignant tumors. Biochimie 87 1005–1010 2005.

  • Minchenko OH Tsymbal DO Minchenko DO Moenner M Kovalevska OV Lypova NM. Inhibition of the endoribonuclease of ERN1 signaling enzyme affects the expression of proliferation-related genes in U87 glioma cells. Endoplasm Reticul Stress Dis 2 18–29 2015b.

  • Minchenko OH Tsymbal DO Minchenko DO Hnatiuk OS Prylutskyy YI Prylutska SV Ritter U. Suppression of the expression of genes associated with immune response in normal human astrocytes upon treatment by single-walled carbon nanotubes. Toxicol In Vitro 52 122–130 2018.

  • Morandi F Cangemi G Barco S Amoroso L Giuliano M Gigliotti AR Pistoia V Corrias MV. Plasma levels of soluble HLA-E and HLA-F at diagnosis may predict overall survival of neuroblastoma patients. Biomed Res Int 2013 956878 2013.

  • Murdaca G Calamaro P Lantieri F Pigozzi S Mastracci L Grillo F Magnani O Ceppa P Puppo F Fiocca R. HLAG expression in gastric carcinoma: clinicopathological correlations and prognostic impact. Virchows Arch 473 425–433 2018.

  • Nair S Lee YH Rousseau E Cam M Tataranni PA Baier LJ Bogardus C Permana PA. Increased expression of inflammation-related genes in cultured preadipocytes/stromal vascular cells from obese compared with nonobese Pima Indians. Diabetologia 48 1784–1788 2005.

  • Ozcan U Cao Q Yilmaz E Lee AH Iwakoshi NN Ozdelen E Tuncman G Gorgun C Glimcher LH Hotamisligil GS. Endoplasmic reticulum stress links obesity insulin action and type 2 diabetes. Science 306 457–461 2004.

  • Pisapia L Cicatiello V Barba P Malanga D Maffei A Hamilton RS Del Pozzo G. Co-regulated expression of alpha and beta mRNAs encoding HLA-DR surface heterodimers is mediated by the MHCII RNA operon. Nucleic Acids Res 41 3772–3786 2013.

  • Richardson SJ Rodriguez-Calvo T Gerling IC Mathews CE Kaddis JS Russell MA Zeissler M Leete P Krogvold L Dahl-Jorgensen K von Herrath M Pugliese A Atkinson MA Morgan NG. Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia 59 2448–2458 2016.

  • Rouas-Freiss N Moreau P LeMaoult J Carosella ED. The dual role of HLA-G in cancer. J Immunol Res 2014 359748 2014.

  • Ruderman NB Carling D Prentki M Cacicedo JM. AMPK insulin resistance and the metabolic syndrome. J Clin Invest 123 2764–2772 2013.

  • Schaiff WT Hruska KA Jr McCourt DW Green M Schwartz BD. HLA-DR associates with specific stress proteins and is retained in the endoplasmic reticulum in invariant chain negative cells. J Exp Med 176 657–666 1992.

  • Shimba S Ogawa T Hitosugi S Ichihashi Y Nakadaira Y Kobayashi M Tezuka M Kosuge Y Ishige K Ito Y Komiyama K Okamatsu-Ogura Y Kimura K Saito M. Deficient of a clock gene brain and muscle Arnt-like protein-1 (BMAL1) induces dyslipidemia and ectopic fat formation. PLoS One 6 e25231 2011.

  • Song Z Krishna S Thanos D Strominger JL Ono SJ. A novel cysteine-rich sequence-specific DNA-binding protein interacts with the conserved X-box motif of the human major histocompatibility complex class II genes via a repeated Cys-His domain and functions as a transcriptional repressor. J Exp Med 180 1763–1774 1994.

  • Sun Z Jha HC Pei YG Robertson ES. Major histocompatibility complex class II HLA-DRα is downregulated by Kaposi’s sarcoma-associated herpesvirus-encoded lytic transactivator RTA and MARCH8. J Virol 90 8047–8058 2016.

  • Tam J Szanda G Drori A Liu Z Cinar R Kashiwaya Y Reitman ML Kunos G. Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling. Mol Metab 6 1113–1125 2017.

  • Tsuchihara K Ogura T Fujioka R Fujii S Kuga W Saito M Ochiya T Ochiai A Esumi H. Susceptibility of Snarkdeficient mice to azoxymethaneinduced colorectal tumorigenesis and the formation of aberrant crypt foci. Cancer Sci 99 677–682 2008.

  • Walentowicz-Sadlecka M Dziobek K Grabiec M Sadlecki P Walentowicz P Mak P Szymankiewicz M Kwinta P Dutsch-Wicherek M. The analysis of human leukocyte antigen-G level in patients with endometrial cancer by Western blot technique. Am J Reprod Immunol 10 e13070 2018.

  • Wang C Cai L Liu J Wang G Li H Wang X Xu W Ren M Feng L Liu P Zhang C. MicroRNA-30a-5p inhibits the growth of renal cell carcinoma by modulating GRP78 expression. Cell Physiol Biochem 43 2405–2419 2017.

  • Wang L Wei B Hu G Wang L Bi M Sun Z Jin Y. Screening of differentially expressed genes associated with human glioblastoma and functional analysis using a DNA microarray. Mol Med Rep 12 1991–1996 2015.

  • Wang M Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529 326–335 2016.

  • Wang S Kaufman RJ. The impact of the unfolded protein response on human disease. J Cell Biol 197 857–867 2012.

  • Winkler MS Rissiek A Priefler M Schwedhelm E Robbe L Bauer A Zahrte C Zoellner C Kluge S Nierhaus A. Human leucocyte antigen (HLA-DR) gene expression is reduced in sepsis and correlates with impaired TNFα response: A diagnostic tool for immunosuppression? PLoS One 12 e0182427 2017.

  • Wu B Yang H Ying S Lu H Wang W Lv J Xiong H Hu W. High HLA-F expression is a poor prognosis factor in patients with nasopharyngeal carcinoma. Anal Cell Pathol (Amst) 2018 7691704 2018.

  • Wu C Xu G Tsai SA Freed WJ Lee CT. Transcriptional profiles of type 2 diabetes in human skeletal muscle reveal insulin resistance metabolic defects apoptosis and molecular signatures of immune activation in response to infections. Biochem Biophys Res Commun 482 282–288 2017.

  • Xu Y Han H Zhang F Lv S Li Z Fang Z. Lesion human leukocyte antigen-F expression is associated with a poor prognosis in patients with hepatocellular carcinoma. Oncol Lett 9 300–304 2013.

  • Yamaoka M Maeda N Nakamura S Kashine S Nakagawa Y Hiuge-Shimizu A Okita K Imagawa A Matsuzawa Y Matsubara K Funahashi T Shimomura I. A pilot investigation of visceral fat adiposity and gene expression profile in peripheral blood cells. PLoS One 7 e47377 2012.

  • Yamashita S Fujii K Zhao C Takagi H Katakura Y. Involvement of the NFX1-repressor complex in PKC-deltainduced repression of hTERT transcription. J Biochem 160 309–313 2016.

  • Yang YC Chang TY Chen TC Lin WS Chang SC Lee YJ. Human leucocyte antigen-G polymorphisms are associated with cervical squamous cell carcinoma risk in Taiwanese women. Eur J Cancer 50 469–474 2014.

  • Yang Z Li H Wang Z Yang Y Niu J Liu Y Sun Z Yin C. Microarray expression profile of long non-coding RNAs in human lung adenocarcinoma. Thorac Cancer 9 1312–1322 2018.

  • Yuzefovych LV Musiyenko SI Wilson GL Rachek LI. Mitochondrial DNA damage and dysfunction and oxidative stress are associated with endoplasmic reticulum stress protein degradation and apoptosis in high fat dietinduced insulin resistance mice. PLoS One 8 e54059 2013.

  • Zhang X Lin A Zhang JG Bao WG Xu DP Ruan YY Yan WH. Alteration of HLA-F and HLA I antigen expression in the tumor is associated with survival in patients with esophageal squamous cell carcinoma. Int J Cancer 132 82–89 2013.

  • Zeestraten EC Reimers MS Saadatmand S Dekker JW Liefers GJ van den Elsen PJ van de Velde CJ Kuppen PJ. Combined analysis of HLA class I HLA-E and HLA-G predicts prognosis in colon cancer patients. Br J Cancer 110 459–468 2014.

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