{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:31:24Z","timestamp":1789777884390,"version":"4.0.1"},"reference-count":50,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T00:00:00Z","timestamp":1756512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"Korean government (MSIT)","doi-asserted-by":"publisher","award":["2018R1A6A1A03025124"],"award-info":[{"award-number":["2018R1A6A1A03025124"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Korean government (MSIT)","doi-asserted-by":"publisher","award":["2020R1A2C1008699"],"award-info":[{"award-number":["2020R1A2C1008699"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Exposure to persistent organic pollutants such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD) increases metabolic disorder risk. In this study, we show that a single intraperitoneal injection of TCDD (10 \u03bcg\/kg) in C57BL\/6J mice induced body weight gain, lipid accumulation in the liver and adipose tissue, macrophage infiltration, and elevated hepatic and serum triglyceride levels after 12 weeks. Despite serum aryl hydrocarbon receptor (AhR) ligand levels normalizing by 12 weeks, the persistent effects suggest TCDD sequestration in fat tissue. TCDD inhibited the expression of mitochondrial proteins (COX1, TOM20, TFAM, H2AX) and reduced mitochondrial oxygen consumption. Liver-specific AhR knockout ameliorated TCDD-induced mitochondrial dysfunction, lipid accumulation, and macrophage infiltration. Mechanistically, TCDD-induced hepatic plasminogen activator inhibitor-1 (PAI-1) promoted adipocyte hypertrophy. In the liver, PAI-1 disrupted the interaction between tissue-type plasminogen activator (tPA) and apolipoprotein B (ApoB), thereby enhancing very-low-density lipoprotein (VLDL) assembly. These findings reveal that hepatocyte-derived circulating PAI-1, upregulated via hepatic AhR activation, contributes to adipocyte hypertrophy and hepatosteatosis through the intracellular modulation of the tPA\u2013PAI-1 axis. Thus, hepatic AhR activation drives mitochondrial dysfunction and obesity, even after a single TCDD exposure.<\/jats:p>","DOI":"10.3390\/ijms26178452","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T15:02:57Z","timestamp":1756825377000},"page":"8452","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hepatic AhR Activation by TCDD Induces Obesity and Steatosis via Hepatic Plasminogen Activator Inhibitor-1 (PAI-1)"],"prefix":"10.3390","volume":"26","author":[{"given":"Seung Jun","family":"Oh","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Department of Physiology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4466-8224","authenticated-orcid":false,"given":"Suyeol","family":"Im","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Department of Physiology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6112-2461","authenticated-orcid":false,"given":"Sora","family":"Kang","sequence":"additional","affiliation":[{"name":"Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Department of Physiology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aden Geonhee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Department of Nutritional Sciences, College of Human Ecology, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2209-6229","authenticated-orcid":false,"given":"Byung Cheol","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Oriental Internal Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7424-3484","authenticated-orcid":false,"given":"Youngmi Kim","family":"Pak","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Department of Physiology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.1016\/j.jada.2005.02.018","article-title":"Beyond energy balance: There is more to obesity than kilocalories","volume":"105","author":"Bray","year":"2005","journal-title":"J. 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