{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:12Z","timestamp":1787027832940,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T00:00:00Z","timestamp":1694649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Regional Initiative of Excellence","award":["002\/RID\/2018\/19"],"award-info":[{"award-number":["002\/RID\/2018\/19"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Sex-dependent patterns in chronic immune-mediated cholangiopathies, like primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), remain poorly understood. Peroxisome proliferator-activated receptor alpha (PPAR-\u03b1), expressed in immune cells, plays a key role in innate defence. In this study, the relationship between PPAR-\u03b1 expression in peripheral blood mononuclear cells (PBMCs), serum androgen levels, IFN\u03b3 production, and sex-dependent tendencies during the development of PBC and PSC was investigated. We confirmed that normal cholangiocytes respond to PPAR-\u03b1 and inhibit the lipopolysaccharide-induced expression of IL-6, IL-1b, and TNF\u03b1. Compared with PSC patients, PPAR-\u03b1 was downregulated, while IFN\u03b3 was upregulated, in the PBMCs of PBC patients. When the analysis was conducted on females only, there was no difference in PPAR-\u03b1, but IFN\u03b3 was elevated in females with PBC compared with those with PSC. Serum testosterone concentrations in females with PBC were below the normal range (regardless of age) and correlated positively with PPAR-\u03b1 and negatively with IFN\u03b3. While PPAR-\u03b1 has been reported to be a target of miR-155 and miR-21, no correlations with these microRNAs were observed in the PBMCs. However, a positive correlation between miR-21 and IFN\u03b3 was observed. Our results showed suppressed PPAR-\u03b1 expression accompanied by reduced testosterone levels in women with PBC, which should elicit interest in the role of testosterone in PBC development.<\/jats:p>","DOI":"10.3390\/cells12182273","type":"journal-article","created":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T03:50:10Z","timestamp":1694749810000},"page":"2273","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Effect of Low Testosterone Levels on the Expression of Proliferator-Activated Receptor Alpha in Female Patients with Primary Biliary Cholangitis"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7513-8640","authenticated-orcid":false,"given":"Agnieszka","family":"Kempi\u0144ska-Podhorodecka","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4190-9901","authenticated-orcid":false,"given":"Joanna","family":"Abramczyk","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliza","family":"Cielica","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartosz","family":"Hu\u0142a","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Maciejowska","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus","family":"Banales","sequence":"additional","affiliation":[{"name":"Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV\/EHU), CIBERehd, Ikerbasque, 20014 San Sebastian, Spain"},{"name":"Department of Biochemistry and Genetics, School of Science, University of Navarra, 31009 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Milkiewicz","sequence":"additional","affiliation":[{"name":"Liver and Internal Medicine Unit, Medical University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2064-0545","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Milkiewicz","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1016\/S0140-6736(20)31607-X","article-title":"Primary biliary cholangitis","volume":"396","author":"Lleo","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2547","DOI":"10.1016\/S0140-6736(18)30300-3","article-title":"Primary sclerosing cholangitis","volume":"391","author":"Dyson","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.3389\/fimmu.2020.01567","article-title":"The Effects of Androgens on T Cells: Clues to Female Predominance in Autoimmune Liver Diseases?","volume":"11","author":"Henze","year":"2020","journal-title":"Front Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sciarra, F., Campolo, F., Franceschini, E., Carlomagno, F., and Venneri, M.A. (2023). Gender-Specific Impact of Sex Hormones on the Immune System. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076302"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"154338","DOI":"10.1016\/j.metabol.2020.154338","article-title":"The role of peroxisome proliferator-activated receptors (PPAR) in immune responses","volume":"114","author":"Christofides","year":"2021","journal-title":"Metabolism"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9505","DOI":"10.1073\/pnas.1118458109","article-title":"Peroxisome proliferator-activated receptor (PPAR)alpha and -gamma regulate IFNgamma and IL-17A production by human T cells in a sex-specific way","volume":"109","author":"Zhang","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1084\/jem.20061839","article-title":"Peroxisome proliferator-activated receptor (PPAR)alpha expression in T cells mediates gender differences in development of T cell-mediated autoimmunity","volume":"204","author":"Dunn","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0014-5793(03)00578-7","article-title":"Hepatic expression of PPAR\u03b1, a molecular target of fibrates, is regulated during inflammation in a gender-specific manner","volume":"546","author":"Tai","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0092-8674(04)00045-5","article-title":"MicroRNAs: Genomics, biogenesis, mechanism, and function","volume":"116","author":"Bartel","year":"2004","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.4049\/jimmunol.1101233","article-title":"MicroRNA regulation of molecular networks mapped by global microRNA, mRNA, and protein expression in activated T lymphocytes","volume":"187","author":"Grigoryev","year":"2011","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1016\/j.jhep.2016.01.035","article-title":"The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis","volume":"64","author":"Bala","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10355","DOI":"10.1073\/pnas.1107052108","article-title":"MicroRNA-21 targets peroxisome proliferators-activated receptor-alpha in an autoregulatory loop to modulate flow-induced endothelial inflammation","volume":"108","author":"Zhou","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1136\/gutjnl-2014-308883","article-title":"Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARalpha expression","volume":"65","author":"Loyer","year":"2016","journal-title":"Gut"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Koenig, A.B., Barajas, J.M., Guerrero, M.J., and Ghoshal, K. (2018). A Comprehensive Analysis of Argonaute-CLIP Data Identifies Novel, Conserved and Species-Specific Targets of miR-21 in Human Liver and Hepatocellular Carcinoma. Int. J. Mol Sci., 19.","DOI":"10.3390\/ijms19030851"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1002\/art.39485","article-title":"In Vivo Therapeutic Success of MicroRNA-155 Antagomir in a Mouse Model of Lupus Alveolar Hemorrhage","volume":"68","author":"Zhou","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Adamowicz, M., Kempinska-Podhorodecka, A., Abramczyk, J., Banales, J.M., Milkiewicz, P., and Milkiewicz, M. (2022). Suppression of Hepatic PPARalpha in Primary Biliary Cholangitis Is Modulated by miR-155. Cells, 11.","DOI":"10.3390\/cells11182880"},{"key":"ref_18","first-page":"G1077","article-title":"Advances in cholangiocyte immunobiology","volume":"303","author":"Syal","year":"2012","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1186\/s12944-018-0901-7","article-title":"Changes in peroxisome proliferator-activated receptor alpha target gene expression in peripheral blood mononuclear cells associated with non-alcoholic fatty liver disease","volume":"17","author":"Li","year":"2018","journal-title":"Lipids Heal. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1002\/hep.27744","article-title":"Fibrates and cholestasis","volume":"62","author":"Ghonem","year":"2015","journal-title":"Hepatology"},{"key":"ref_21","first-page":"35","article-title":"Androgens Alter the Cytokine Profile and Reduce Encephalitogenicity of Myelin-Reactive T Cells","volume":"162","author":"Bebo","year":"1999","journal-title":"Pediatrics"},{"key":"ref_22","first-page":"2060","article-title":"Testosterone Acts Directly on CD4+ T Lymphocytes to Increase IL-10 Production","volume":"167","author":"Liva","year":"2001","journal-title":"Pediatrics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6237","DOI":"10.4049\/jimmunol.164.12.6237","article-title":"Gender-Dependent IL-12 Secretion by APC Is Regulated by IL-10","volume":"164","author":"Wilcoxen","year":"2000","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1172\/JCI92885","article-title":"Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males","volume":"127","author":"Pace","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1111\/j.1749-6632.1999.tb07667.x","article-title":"Sex hormones modulate inflammatory mediators produced by macrophages","volume":"876","author":"Milano","year":"1999","journal-title":"Ann. N. Y. Acad Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1097\/00000441-199510000-00006","article-title":"Case Report: Testosterone Treatment of Systemic Lupus Erythematosus in a Patient With Klinefelter\u2019s Syndrome","volume":"310","author":"Olsen","year":"1995","journal-title":"Am. J. Med Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1001\/archneur.64.5.683","article-title":"Testosterone treatment in multiple sclerosis: A pilot study","volume":"64","author":"Sicotte","year":"2007","journal-title":"Arch. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1093\/rheumatology\/35.6.568","article-title":"A randomized trial of testosterone therapy in males with rheumatoid arthritis","volume":"35","author":"Hall","year":"1996","journal-title":"Rheumatology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1210\/jc.2009-0106","article-title":"Low Serum Levels of Sex Steroids Are Associated with Disease Characteristics in Primary Sjogren\u2019s Syndrome; Supplementation with Dehydroepiandrosterone Restores the Concentrations","volume":"94","author":"Carlsten","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/S0301-2115(02)00046-5","article-title":"Sex hormone profile and endometrial cancer risk in primary biliary cirrhosis: A case-control study","volume":"103","author":"Floreani","year":"2002","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1093\/humupd\/dmt038","article-title":"The effect of combined oral contraception on testosterone levels in healthy women: A systematic review and meta-analysis","volume":"20","author":"Zimmerman","year":"2013","journal-title":"Hum. Reprod. Updat."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/j.1749-6632.2002.tb04210.x","article-title":"Androgens and Estrogens Modulate the Immune and Inflammatory Responses in Rheumatoid Arthritis","volume":"966","author":"Cutolo","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kilanczyk, E., Ruminkiewicz, D., Banales, J.M., Milkiewicz, P., and Milkiewicz, M. (2022). DHEA Protects Human Cholangiocytes and Hepatocytes against Apoptosis and Oxidative Stress. Cells, 11.","DOI":"10.3390\/cells11061038"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"G981","DOI":"10.1152\/ajpgi.00061.2011","article-title":"Castration inhibits biliary proliferation induced by bile duct obstruction: Novel role for the autocrine trophic effect of testosterone","volume":"301","author":"Yang","year":"2011","journal-title":"Am. J. Physiol Gastrointest. Liver Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1091\/mbc.E14-08-1323","article-title":"Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells","volume":"26","author":"Walecki","year":"2015","journal-title":"Mol. Biol. Cell."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1172\/JCI108729","article-title":"Androgenic Hormones Modulate Autoantibody Responses and Improve Survival in Murine Lupus","volume":"59","author":"Roubinian","year":"1977","journal-title":"J. Clin. Investig."},{"key":"ref_37","first-page":"3","article-title":"Testosterone therapy ameliorates experimental autoimmune encephalomyelitis and induces a T helper 2 bias in the autoantigen-specific T lymphocyte response","volume":"159","author":"Dalal","year":"1997","journal-title":"Pediatrics"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Lotter, H., Helk, E., Bernin, H., Jacobs, T., Prehn, C., Adamski, J., Gonzalez-Roldan, N., Holst, O., and Tannich, E. (2013). Testosterone increases susceptibility to amebic liver abscess in mice and mediates inhibition of IFNgamma secretion in natural killer T cells. PLoS. ONE, 8.","DOI":"10.1371\/journal.pone.0055694"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.4049\/jimmunol.1400076","article-title":"Testosterone suppresses hepatic inflammation by the downregulation of IL-17, CXCL-9, and CXCL-10 in a mouse model of experimental acute cholangitis","volume":"194","author":"Schwinge","year":"2015","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/ni.1828","article-title":"Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21","volume":"11","author":"Sheedy","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3389\/fimmu.2015.00019","article-title":"Turning 21: Induction of miR-21 as a Key Switch in the Inflammatory Response","volume":"6","author":"Sheedy","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3362","DOI":"10.4049\/jimmunol.1101235","article-title":"MicroRNA-21 limits in vivo immune response-mediated activation of the IL-12\/IFN-\u03b3 pathway, Th1 polarization, and the severity of delayed-type hypersensitivity","volume":"187","author":"Lu","year":"2011","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.4049\/jimmunol.2001099","article-title":"MicroRNA-21 Deficiency Promotes the Early Th1 Immune Response and Resistance toward Visceral Leishmaniasis","volume":"207","author":"Varikuti","year":"2021","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8108","DOI":"10.1158\/0008-5472.CAN-10-2579","article-title":"IFN Induces miR-21 through a Signal Transducer and Activator of Transcription 3\u2013Dependent Pathway as a Suppressive Negative Feedback on IFN-Induced Apoptosis","volume":"70","author":"Yang","year":"2010","journal-title":"Cancer Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/18\/2273\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:50:54Z","timestamp":1760129454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/18\/2273"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,14]]},"references-count":44,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["cells12182273"],"URL":"https:\/\/doi.org\/10.3390\/cells12182273","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,14]]}}}