{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T07:21:06Z","timestamp":1785223266651,"version":"3.55.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2019,6,21]],"date-time":"2019-06-21T00:00:00Z","timestamp":1561075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ES004869"],"award-info":[{"award-number":["ES004869"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ES028244"],"award-info":[{"award-number":["ES028244"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"USDA National Institute of Food and Federal Appropriations","award":["PEN04607"],"award-info":[{"award-number":["PEN04607"]}]},{"name":"USDA National Institute of Food and Federal Appropriations","award":["1009993"],"award-info":[{"award-number":["1009993"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The aryl hydrocarbon receptor (AHR) mediates 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity that can lead to chloracne in humans. A characteristic of chloracne, in contrast to acne vulgaris, is shrinkage or loss of sebaceous glands. Acne vulgaris, on the other hand, is often accompanied by excessive sebum production. Here, we examined the role of AHR in lipid synthesis in human sebocytes using distinct classes of AHR ligands. Modulation of AHR activity attenuated the expression of lipogenic genes and key proinflammatory markers in the absence of canonical DRE-driven transcription of the AHR target gene CYP1A1. Furthermore, topical treatment with TCDD, which mediates DRE-dependent activity, and SGA360, which fails to induce DRE-mediated responses, both exhibited a decrease in the size of sebaceous glands and the number of sebocytes within each gland in the skin. To elucidate the mechanism of AHR-mediated repression of lipid synthesis, we demonstrated that selective AHR modulators, SGA360 and SGA315 increased the protein turnover of the mature sterol regulatory element-binding protein (mSREBP-1), the principal transcriptional regulator of the fatty acid synthesis pathway. Interestingly, selective AHR ligand treatment significantly activated the AMPK-dependent kinase (AMPK) in sebocytes. Moreover, we demonstrated an inverse correlation between the active AMPK and the mSREBP-1 protein, which is consistent with the previously reported role of AMPK in inhibiting cleavage of SREBP-1. Overall, our findings indicate a DRE-independent function of selective AHR ligands in modulating lipid synthesis in human sebocytes, which might raise the possibility of using AHR as a therapeutic target for treatment of acne.<\/jats:p>","DOI":"10.1093\/toxsci\/kfz140","type":"journal-article","created":{"date-parts":[[2019,6,13]],"date-time":"2019-06-13T15:13:38Z","timestamp":1560438818000},"page":"146-158","source":"Crossref","is-referenced-by-count":18,"title":["Selective Ah Receptor Ligands Mediate Enhanced SREBP1 Proteolysis to Restrict Lipogenesis in Sebocytes"],"prefix":"10.1093","volume":"171","author":[{"given":"Gulsum E","family":"Muku","sequence":"first","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Blazanin","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangcong","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip B","family":"Smith","sequence":"additional","affiliation":[{"name":"The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Thiboutot","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Penn State College of Medicine, Hershey, Pennsylvania 17033"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishne","family":"Gowda","sequence":"additional","affiliation":[{"name":"Department of Pharmacology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shantu","family":"Amin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain A","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary H","family":"Perdew","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,6,21]]},"reference":[{"key":"2019091012224241900_kfz140-B1","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1093\/toxsci\/kfs277","article-title":"TCDD-elicited effects on liver, serum, and adipose lipid composition in C57BL\/6 mice","volume":"131","author":"Angrish","year":"2013","journal-title":"Toxicol. Sci"},{"key":"2019091012224241900_kfz140-B2","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1111\/bjd.12149","article-title":"Epidemiology of acne vulgaris","volume":"168","author":"Bhate","year":"2013","journal-title":"Br. J. Dermatol"},{"key":"2019091012224241900_kfz140-B3","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/978-1-60761-322-0_22","article-title":"Comprehensive quantitative analysis of bioactive sphinolipids by high-performance liquid chromatography-tandem mass spectrometry","volume":"579","author":"Bielawski","year":"2009","journal-title":"Methods Mol. Biol"},{"key":"2019091012224241900_kfz140-B4","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1007\/s00204-017-1965-2","article-title":"2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated deregulation of myeloid and sebaceous gland stem\/progenitor cell homeostasis","volume":"91","author":"Bock","year":"2017","journal-title":"Arch. Toxicol"},{"key":"2019091012224241900_kfz140-B5","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1038\/jid.2015.6","article-title":"Genetic and pharmacological analysis identifies a physiological role for the AHR in epidermal differentiation","volume":"135","author":"van den Bogaard","year":"2015","journal-title":"J. Invest. Dermatol"},{"key":"2019091012224241900_kfz140-B6","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/S0006-291X(85)80158-3","article-title":"TCDD (2, 3, 7, 8-tetrachlorodibenzo-p-dioxin) causes increases in protein kinases particularly protein kinase C in the hepatic plasma membrane of the rat and the guinea pig","volume":"127","author":"Bombick","year":"1985","journal-title":"Biochem. Biophys. Res. Commun"},{"key":"2019091012224241900_kfz140-B7","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1002\/jbt.2570020207","article-title":"2,3,7,8-Tetrachlorodibenzo-p-dioxin causes elevation of the levels of the protein tyrosine kinase pp60c-src","volume":"2","author":"Bombick","year":"1987","journal-title":"J. Biochem. Toxicol"},{"key":"2019091012224241900_kfz140-B8","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1194\/jlr.R800054-JLR200","article-title":"Cholesterol feedback: from Schoenheimer\u2019s bottle to Scap\u2019s MELADL","volume":"50","author":"Brown","year":"2009","journal-title":"J. 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Dermatol. Res"},{"key":"2019091012224241900_kfz140-B12","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1172\/JCI42974","article-title":"Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation","volume":"121","author":"Cui","year":"2011","journal-title":"J. Clin. 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Dermatol"},{"key":"2019091012224241900_kfz140-B17","doi-asserted-by":"crossref","first-page":"726.","DOI":"10.1001\/jama.292.6.726","article-title":"Treatment of acne vulgaris","volume":"292","author":"Haider","year":"2004","journal-title":"JAMA"},{"key":"2019091012224241900_kfz140-B301","volume":"258"},{"key":"2019091012224241900_kfz140-B18","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1111\/j.1600-0625.2010.01204.x","article-title":"2,3,7,8-Tetrachlorodibenzo-p-dioxin alters sebaceous gland cell differentiation in vitro","volume":"20","author":"Ju","year":"2011","journal-title":"Exp. Dermatol"},{"key":"2019091012224241900_kfz140-B19","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1111\/j.1600-0625.2009.00890.x","article-title":"New developments in our understanding of acne pathogenesis and treatment","volume":"18","author":"Kurokawa","year":"2009","journal-title":"Exp. 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Chem"},{"key":"2019091012224241900_kfz140-B25","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1038\/labinvest.2017.92","article-title":"Ligand-mediated cytoplasmic retention of the Ah receptor inhibits macrophage-mediated acute inflammatory responses","volume":"97","author":"Muku","year":"2017","journal-title":"Lab. Invest"},{"key":"2019091012224241900_kfz140-B26","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1021\/tx100045h","article-title":"Development of a selective modulator of aryl hydrocarbon (Ah) receptor activity that exhibits anti-inflammatory properties","volume":"23","author":"Murray","year":"2010","journal-title":"Chem. Res. Toxicol"},{"key":"2019091012224241900_kfz140-B27","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.taap.2012.11.028","article-title":"Comparison of TCDD-elicited genome-wide hepatic gene expression in Sprague\u2013Dawley rats and C57BL\/6 mice","volume":"267","author":"Nault","year":"2013","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"2019091012224241900_kfz140-B28","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.semcdb.2012.08.010","article-title":"Development and homeostasis of the sebaceous gland","volume":"23","author":"Niemann","year":"2012","journal-title":"Semin. Cell Dev. Biol"},{"key":"2019091012224241900_kfz140-B29","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/nature05683","article-title":"Dioxin receptor is a ligand-dependent E3 ubiquitin ligase","volume":"446","author":"Ohtake","year":"2007","journal-title":"Nature"},{"key":"2019091012224241900_kfz140-B30","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.bcp.2008.08.034","article-title":"AhR acts as an E3 ubiquitin ligase to modulate steroid receptor functions","volume":"77","author":"Ohtake","year":"2009","journal-title":"Biochem. Pharmacol"},{"key":"2019091012224241900_kfz140-B31","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0009-2797(02)00064-9","article-title":"The role of chaperone proteins in the aryl hydrocarbon receptor core complex","volume":"141","author":"Petrulis","year":"2002","journal-title":"Chem. Biol. Interact"},{"key":"2019091012224241900_kfz140-B32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tox.2009.08.017","article-title":"Inflammatory and chloracne-like skin lesions in B6C3F1 mice exposed to 3,3\u2019,4,4\u2019-tetrachloroazobenzene for 2 years","volume":"265","author":"Ramot","year":"2009","journal-title":"Toxicology"},{"key":"2019091012224241900_kfz140-B33","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1093\/toxsci\/kfr223","article-title":"The cutaneous lesions of dioxin exposure: Lessons from the poisoning of victor yushchenko","volume":"125","author":"Saurat","year":"2012","journal-title":"Toxicol. Sci"},{"key":"2019091012224241900_kfz140-B34","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1159\/000290672","article-title":"Chloracne, a misnomer and its implications","volume":"221","author":"Saurat","year":"2010","journal-title":"Dermatology"},{"key":"2019091012224241900_kfz140-B35","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1093\/toxsci\/kfx160","article-title":"Editor's highlight: Ah receptor activation potentiates neutrophil chemoattractant (C-X-C motif) ligand 5 expression in keratinocytes and skin","volume":"160","author":"Smith","year":"2017","journal-title":"Toxicol. Sci"},{"key":"2019091012224241900_kfz140-B36","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1194\/jlr.R700015-JLR200","article-title":"Thematic review series: Skin Lipids. Sebaceous gland lipids: Friend or foe?","volume":"49","author":"Smith","year":"2008","journal-title":"J. Lipid Res"},{"key":"2019091012224241900_kfz140-B37","doi-asserted-by":"crossref","first-page":"165","DOI":"10.5271\/sjweh.2240","article-title":"Chloracne, \u201cthe hallmark of dioxin intoxication\u201d","volume":"11","author":"Suskind","year":"1985","journal-title":"Scand. J. Work. Environ. Health"},{"key":"2019091012224241900_kfz140-B38","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1093\/toxsci\/kfs204","article-title":"Role of the Ah receptor in homeostatic control of fatty acid synthesis in the liver","volume":"129","author":"Tanos","year":"2012","journal-title":"Toxicol. 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Role of peroxynitrite","volume":"278","author":"Zou","year":"2003","journal-title":"J. Biol. Chem"},{"key":"2019091012224241900_kfz140-B46","doi-asserted-by":"crossref","first-page":"43940","DOI":"10.1074\/jbc.M404421200","article-title":"Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species","volume":"279","author":"Zou","year":"2004","journal-title":"J. Biol. 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