{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T01:39:15Z","timestamp":1781055555486,"version":"3.54.1"},"reference-count":48,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,8,5]],"date-time":"2023-08-05T00:00:00Z","timestamp":1691193600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Swedish Research Council","award":["E-0004"],"award-info":[{"award-number":["E-0004"]}]},{"DOI":"10.13039\/100000928","name":"Robert A. Welch Foundation","doi-asserted-by":"publisher","award":["E-0004"],"award-info":[{"award-number":["E-0004"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Liver X receptors (LXR\u03b1 and LXR\u03b2) are oxysterol-activated nuclear receptors that play key roles in cholesterol homeostasis, the central nervous system, and the immune system. We have previously reported that LXR\u03b1\u03b2-deficient mice are more susceptible to dextran sodium sulfate (DSS)-induced colitis than their WT littermates, and that an LXR agonist protects against colitis in mice mainly via the regulation of the immune system in the gut. We now report that both LXR\u03b1 and LXR\u03b2 are expressed in the colonic epithelium and that in aging LXR\u03b1\u03b2\u2212\/\u2212 mice there is a reduction in the intensity of goblet cells, mucin (MUC2), TFF3, and estrogen receptor \u03b2 (ER\u03b2) levels. The cytoplasmic compartment of the surface epithelial cells was markedly reduced and there was a massive invasion of macrophages in the lamina propria. The expression and localization of \u03b2-catenin, \u03b1-catenin, and E-cadherin were not changed, but the shrinkage of the cytoplasm led to an appearance of an increase in staining. In the colonic epithelium there was a reduction in the expression of plectin, a hemidesmosome protein whose loss in mice leads to spontaneous colitis, ELOVL1, a fatty acid elongase protein coding gene whose overexpression is found in colorectal cancer, and non-neuronal choline acetyltransferase (ChAT) involved in the regulation of epithelial cell adhesion. We conclude that in aging LXR\u03b1\u03b2\u2212\/\u2212 mice, the phenotype in the colon is due to loss of ER\u03b2 expression.<\/jats:p>","DOI":"10.3390\/ijms241512461","type":"journal-article","created":{"date-parts":[[2023,8,5]],"date-time":"2023-08-05T10:21:39Z","timestamp":1691230899000},"page":"12461","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Loss of ER\u03b2 in Aging LXR\u03b1\u03b2 Knockout Mice Leads to Colitis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9485-977X","authenticated-orcid":false,"given":"Xiaoyu","family":"Song","sequence":"first","affiliation":[{"name":"Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanfu","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubing","family":"Dai","sequence":"additional","affiliation":[{"name":"Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Warner","sequence":"additional","affiliation":[{"name":"Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6828-2583","authenticated-orcid":false,"given":"Ivan","family":"Nalvarte","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Nutrition, Karolinska Institutet, 14186 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9335-9941","authenticated-orcid":false,"given":"Per","family":"Antonson","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Nutrition, Karolinska Institutet, 14186 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2165-0152","authenticated-orcid":false,"given":"Mukesh","family":"Varshney","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Nutrition, Karolinska Institutet, 14186 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan-\u00c5ke","family":"Gustafsson","sequence":"additional","affiliation":[{"name":"Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA"},{"name":"Department of Biosciences and Nutrition, Karolinska Institutet, 14186 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/imm.13117","article-title":"Intestinal epithelial cells: At the interface of the microbiota and mucosal immunity","volume":"158","author":"Soderholm","year":"2019","journal-title":"Immunology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.tips.2012.03.013","article-title":"Liver X receptor biology and pharmacology: New pathways, challenges and opportunities","volume":"33","author":"Jakobsson","year":"2012","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Song, X., Wu, W., Warner, M., and Gustafsson, J.A. (2022). Liver X Receptor Regulation of Glial Cell Functions in the CNS. Biomedicines, 10.","DOI":"10.3390\/biomedicines10092165"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1515\/bmc-2015-0007","article-title":"Liver X receptors as regulators of metabolism","volume":"6","author":"Gustafsson","year":"2015","journal-title":"Biomol. Concepts"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1517\/14728222.2013.806490","article-title":"Targeting liver X receptors in inflammation","volume":"17","author":"Steffensen","year":"2013","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"de Freitas, F.A., Levy, D., Reichert, C.O., Cunha-Neto, E., Kalil, J., and Bydlowski, S.P. (2022). Effects of Oxysterols on Immune Cells and Related Diseases. Cells, 11.","DOI":"10.3390\/cells11081251"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4917","DOI":"10.1111\/bph.15479","article-title":"The oxysterome and its receptors as pharmacological targets in inflammatory diseases","volume":"179","author":"Muccioli","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_8","first-page":"2570","article-title":"Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases","volume":"30","author":"Yu","year":"2016","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1093\/ibd\/izab034","article-title":"Liver X Receptor Exerts Anti-Inflammatory Effects in Colonic Epithelial Cells via ABCA1 and Its Expression Is Decreased in Human and Experimental Inflammatory Bowel Disease","volume":"27","author":"Puerto","year":"2021","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"197","DOI":"10.3748\/wjg.v17.i2.197","article-title":"Polymorphisms in NF-kappaB, PXR, LXR, PPARgamma and risk of inflammatory bowel disease","volume":"17","author":"Andersen","year":"2011","journal-title":"World J. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1038\/mi.2014.31","article-title":"The oxysterol receptor LXRbeta protects against DSS- and TNBS-induced colitis in mice","volume":"7","author":"Jakobsson","year":"2014","journal-title":"Mucosal Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1042\/EBC20210010","article-title":"Estrogen receptor actions in colitis","volume":"65","author":"Allred","year":"2021","journal-title":"Essays Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1073\/pnas.0511271103","article-title":"Role of estrogen receptor beta in colonic epithelium","volume":"103","author":"Imamov","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s40168-022-01356-2","article-title":"Estrogen receptor beta deficiency impairs gut microbiota: A possible mechanism of IBD-induced anxiety-like behavior","volume":"10","author":"Ma","year":"2022","journal-title":"Microbiome"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.canlet.2020.06.021","article-title":"Intestinal estrogen receptor beta suppresses colon inflammation and tumorigenesis in both sexes","volume":"492","author":"Hases","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2848","DOI":"10.7150\/ijbs.85164","article-title":"Liver X receptors and estrogen receptor beta, two players in a rare subtype of NSCLC","volume":"19","author":"Wu","year":"2023","journal-title":"Int. J. Biol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13445","DOI":"10.1073\/pnas.0806974105","article-title":"Expression of liver X receptor beta is essential for formation of superficial cortical layers and migration of later-born neurons","volume":"105","author":"Fan","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1073\/pnas.0811295106","article-title":"Stromal growth and epithelial cell proliferation in ventral prostates of liver X receptor knockout mice","volume":"106","author":"Kim","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14006","DOI":"10.1073\/pnas.1519358112","article-title":"Liver X receptor beta controls thyroid hormone feedback in the brain and regulates browning of subcutaneous white adipose tissue","volume":"112","author":"Miao","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1038\/mp.2015.133","article-title":"Liver X receptors regulate cerebrospinal fluid production","volume":"21","author":"Dai","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16507","DOI":"10.1073\/pnas.1904719116","article-title":"Retinal and optic nerve degeneration in liver X receptor beta knockout mice","volume":"116","author":"Song","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"108534","DOI":"10.1016\/j.heares.2022.108534","article-title":"Ablation of Liver X receptor beta in mice leads to overactive macrophages and death of spiral ganglion neurons","volume":"422","author":"Song","year":"2022","journal-title":"Hear. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1146\/annurev-physiol-021115-105447","article-title":"Trefoil Factor Peptides and Gastrointestinal Function","volume":"79","author":"Aihara","year":"2017","journal-title":"Annu. Rev. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1016\/j.jcmgh.2021.08.021","article-title":"The Role of Intestinal Macrophages in Gastrointestinal Homeostasis: Heterogeneity and Implications in Disease","volume":"12","author":"Yip","year":"2021","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1159\/000355835","article-title":"The non-neuronal cholinergic system in health and disease","volume":"92","author":"Beckmann","year":"2013","journal-title":"Pharmacology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"G966","DOI":"10.1152\/ajpgi.00087.2018","article-title":"Knockout of ClC-2 reveals critical functions of adherens junctions in colonic homeostasis and tumorigenicity","volume":"315","author":"Jin","year":"2018","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Castanon, M.J., and Wiche, G. (2021). Identifying Plectin Isoform Functions through Animal Models. Cells, 10.","DOI":"10.3390\/cells10092453"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kiritsi, D., Tsakiris, L., and Schauer, F. (2021). Plectin in Skin Fragility Disorders. Cells, 10.","DOI":"10.3390\/cells10102738"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/s41385-021-00380-z","article-title":"Plectin ensures intestinal epithelial integrity and protects colon against colitis","volume":"14","author":"Krausova","year":"2021","journal-title":"Mucosal Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1136\/gutjnl-2015-310847","article-title":"Hemidesmosome integrity protects the colon against colitis and colorectal cancer","volume":"66","author":"Hamade","year":"2017","journal-title":"Gut"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2964","DOI":"10.1101\/gad.8.24.2964","article-title":"Colorectal hyperplasia and inflammation in keratin 8-deficient FVB\/N mice","volume":"8","author":"Baribault","year":"1994","journal-title":"Genes Dev."},{"key":"ref_32","first-page":"e22165","article-title":"The nonneuronal cholinergic system in the colon: A comprehensive review","volume":"36","author":"Li","year":"2022","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ejphar.2014.03.036","article-title":"Choline acetyltransferase and organic cation transporters are responsible for synthesis and propionate-induced release of acetylcholine in colon epithelium","volume":"733","author":"Bader","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1159\/000345437","article-title":"Cholinergic modulation of epithelial integrity in the proximal colon of pigs","volume":"197","author":"Lesko","year":"2013","journal-title":"Cells Tissues Organs"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1002\/ibd.20224","article-title":"Presence of a marked nonneuronal cholinergic system in human colon: Study of normal colon and colon in ulcerative colitis","volume":"13","author":"Jonsson","year":"2007","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1007\/s00424-018-2236-7","article-title":"Robustness of the non-neuronal cholinergic system in rat large intestine against luminal challenges","volume":"471","author":"Bader","year":"2019","journal-title":"Pflug. Arch. Eur. J. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1007\/s00424-017-2104-x","article-title":"Segmental differences in the non-neuronal cholinergic system in rat caecum","volume":"470","author":"Bader","year":"2018","journal-title":"Pflug. Arch. Eur. J. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1128\/MCB.00192-13","article-title":"Impaired epidermal permeability barrier in mice lacking elovl1, the gene responsible for very-long-chain fatty acid production","volume":"33","author":"Sassa","year":"2013","journal-title":"Mol. Cell. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6507","DOI":"10.1002\/jcp.30325","article-title":"DOCK4 stimulates MUC2 production through its effect on goblet cell differentiation","volume":"236","author":"Qin","year":"2021","journal-title":"J. Cell. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6434","DOI":"10.1074\/jbc.M512905200","article-title":"Vangl1 protein acts as a downstream effector of intestinal trefoil factor (ITF)\/TFF3 signaling and regulates wound healing of intestinal epithelium","volume":"281","author":"Kalabis","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"13112","DOI":"10.1073\/pnas.1210833109","article-title":"Liver X receptor beta protects dopaminergic neurons in a mouse model of Parkinson disease","volume":"109","author":"Dai","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3857","DOI":"10.1073\/pnas.0500634102","article-title":"Inactivation of liver X receptor beta leads to adult-onset motor neuron degeneration in male mice","volume":"102","author":"Andersson","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7614","DOI":"10.1073\/pnas.1607590113","article-title":"Ablation of Liver X receptors alpha and beta leads to spontaneous peripheral squamous cell lung cancer in mice","volume":"113","author":"Dai","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/978-3-031-11836-4_12","article-title":"ERbeta and Inflammation","volume":"1390","author":"Hases","year":"2022","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"682","DOI":"10.5009\/gnl18221","article-title":"Effects of 17beta-Estradiol on Colonic Permeability and Inflammation in an Azoxymethane\/Dextran Sulfate Sodium-Induced Colitis Mouse Model","volume":"12","author":"Song","year":"2018","journal-title":"Gut Liver"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3248","DOI":"10.1002\/ptr.7495","article-title":"Phytoestrogen arctigenin preserves the mucus barrier in inflammatory bowel diseases by inhibiting goblet cell apoptosis via the ERbeta\/TRIM21\/PHB1 pathway","volume":"36","author":"Tao","year":"2022","journal-title":"Phytother. Res. PTR"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Polari, L., Anttila, S., Helenius, T., Wiklund, A., Linnanen, T., Toivola, D.M., and Maatta, J. (2019). Novel Selective Estrogen Receptor Modulator Ameliorates Murine Colitis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20123007"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1172\/JCI9794","article-title":"Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRbeta-deficient mice","volume":"107","author":"Alberti","year":"2001","journal-title":"J. Clin. Investig."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/12461\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:26:26Z","timestamp":1760127986000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/12461"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,5]]},"references-count":48,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241512461"],"URL":"https:\/\/doi.org\/10.3390\/ijms241512461","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,5]]}}}