Molecular mechanisms of dose-dependent regulation of hepatic lipid metabolism by BaP through modulation of AhR binding to XRE1 or XRE3
Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon and a potent environmental pollutant, has been implicated in the dysregulation of lipid metabolism and metabolic diseases, warranting investigation into its effects on liver functions, particularly regarding fibroblast growth factor 21 (FGF21)...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1595566/full |
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| author | Mengdi Zhang Mengdi Zhang Xiaoli Lv Xiaoli Lv Chaojie Wang Chaojie Wang Lei Wang Lei Wang Han Wang Han Wang Xue Wang Xue Wang Yulu Du Yulu Du Jun Li Jun Li Jun Li Xiuli Han Xiuli Han Xiuli Han Lei Fan Lei Fan Yuxia Hu Yuxia Hu Yuxia Hu Tuya Bai Tuya Bai Weizhong Huangfu Fuhou Chang Fuhou Chang |
| author_facet | Mengdi Zhang Mengdi Zhang Xiaoli Lv Xiaoli Lv Chaojie Wang Chaojie Wang Lei Wang Lei Wang Han Wang Han Wang Xue Wang Xue Wang Yulu Du Yulu Du Jun Li Jun Li Jun Li Xiuli Han Xiuli Han Xiuli Han Lei Fan Lei Fan Yuxia Hu Yuxia Hu Yuxia Hu Tuya Bai Tuya Bai Weizhong Huangfu Fuhou Chang Fuhou Chang |
| author_sort | Mengdi Zhang |
| collection | DOAJ |
| description | Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon and a potent environmental pollutant, has been implicated in the dysregulation of lipid metabolism and metabolic diseases, warranting investigation into its effects on liver functions, particularly regarding fibroblast growth factor 21 (FGF21) mediated pathways. This study aimed to elucidate the effects of BaP on liver lipid metabolism and FGF21 expression via the aryl hydrocarbon receptor (AhR), with a focus on the regulatory interactions between BaP and xenobiotic response elements (XRE) within the promoter region of FGF21. Utilizing HepG2 cells, lipid accumulation was assessed through Oil Red O and Nile Red staining, while the expression of FGF21 protein was quantified by Western blotting and immunofluorescence techniques. Additionally, various truncated plasmids of the FGF21 promoter were synthesized for a dual-luciferase reporter assay to determine the relative luciferase activity and the modulation of FGF21 expression by BaP. The results revealed dose-dependent effects of BaP on lipid metabolism; specifically, low concentrations of BaP upregulated FGF21 expression by enhancing promoter activity in regions containing the XRE1 sequence, whereas higher BaP concentrations downregulated FGF21 expression via inhibition of promoter activity in regions with the XRE3 sequence. In conclusion, low doses of BaP facilitate AhR binding to XRE1, promoting FGF21 expression, while high doses disrupt this interaction through XRE3, culminating in decreased expression levels. These findings suggest a nuanced role of BaP in lipid metabolism regulation, with potential implications for understanding metabolic disorders associated with environmental pollutants. The study elucidates the relationship between AhR and FGF-21, providing an experimental basis for the search of new targets for the prevention and treatment of nonalcoholic fatty liver disease (NAFLD). |
| format | Article |
| id | doaj-art-3133146cded445efb8b7ced76f856bde |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-3133146cded445efb8b7ced76f856bde2025-08-20T03:55:48ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-07-011610.3389/fphar.2025.15955661595566Molecular mechanisms of dose-dependent regulation of hepatic lipid metabolism by BaP through modulation of AhR binding to XRE1 or XRE3Mengdi Zhang0Mengdi Zhang1Xiaoli Lv2Xiaoli Lv3Chaojie Wang4Chaojie Wang5Lei Wang6Lei Wang7Han Wang8Han Wang9Xue Wang10Xue Wang11Yulu Du12Yulu Du13Jun Li14Jun Li15Jun Li16Xiuli Han17Xiuli Han18Xiuli Han19Lei Fan20Lei Fan21Yuxia Hu22Yuxia Hu23Yuxia Hu24Tuya Bai25Tuya Bai26Weizhong Huangfu27Fuhou Chang28Fuhou Chang29College of Pharmacy, Inner Mongolia Medical University, Hohhot, ChinaInner Mongolia Autonomous Region Engineering Research Center of New Pharmaceutical Screening, Inner Mongolia Medical University, Hohhot, ChinaCollege of Pharmacy, Inner Mongolia Medical University, Hohhot, ChinaInner Mongolia Autonomous Region Engineering Research Center of New Pharmaceutical Screening, Inner Mongolia Medical University, Hohhot, ChinaCollege of Pharmacy, Inner Mongolia Medical University, Hohhot, ChinaInner Mongolia Autonomous Region Engineering Research Center of New Pharmaceutical Screening, Inner Mongolia Medical University, Hohhot, ChinaCollege of Pharmacy, Inner Mongolia Medical University, Hohhot, ChinaInner Mongolia Autonomous Region Engineering Research Center of New Pharmaceutical Screening, Inner Mongolia Medical University, Hohhot, ChinaCollege of Pharmacy, Inner Mongolia Medical University, Hohhot, ChinaInner Mongolia Autonomous Region Engineering Research Center of New Pharmaceutical Screening, Inner Mongolia Medical University, Hohhot, ChinaCollege of Pharmacy, Inner Mongolia Medical University, Hohhot, ChinaInner Mongolia Autonomous Region Engineering Research Center of New Pharmaceutical Screening, Inner Mongolia Medical University, Hohhot, ChinaCollege of Pharmacy, Inner Mongolia Medical University, Hohhot, ChinaInner Mongolia Autonomous Region Engineering Research Center of New Pharmaceutical Screening, Inner Mongolia Medical University, Hohhot, ChinaCollege of Pharmacy, Inner Mongolia Medical University, Hohhot, ChinaInner Mongolia Autonomous Region Engineering Research Center of New Pharmaceutical Screening, Inner Mongolia Medical University, Hohhot, ChinaCenter for New Drug Safety Evaluation and Research, Inner Mongolia Medical University, Hohhot, ChinaCollege of Pharmacy, Inner Mongolia Medical University, Hohhot, ChinaInner Mongolia Autonomous Region Engineering Research Center of New Pharmaceutical Screening, Inner Mongolia Medical University, Hohhot, ChinaCenter for New Drug Safety Evaluation and Research, Inner Mongolia Medical University, Hohhot, ChinaCollege of Pharmacy, Inner Mongolia Medical University, Hohhot, ChinaInner Mongolia Autonomous Region Engineering Research Center of New Pharmaceutical Screening, Inner Mongolia Medical University, Hohhot, ChinaCollege of Pharmacy, Inner Mongolia Medical University, Hohhot, ChinaInner Mongolia Autonomous Region Engineering Research Center of New Pharmaceutical Screening, Inner Mongolia Medical University, Hohhot, ChinaCenter for New Drug Safety Evaluation and Research, Inner Mongolia Medical University, Hohhot, ChinaCollege of Pharmacy, Inner Mongolia Medical University, Hohhot, ChinaInner Mongolia Autonomous Region Engineering Research Center of New Pharmaceutical Screening, Inner Mongolia Medical University, Hohhot, ChinaAffiliated Hospital of Inner Mongolia Medical University, Hohhot, ChinaCollege of Pharmacy, Inner Mongolia Medical University, Hohhot, ChinaInner Mongolia Autonomous Region Engineering Research Center of New Pharmaceutical Screening, Inner Mongolia Medical University, Hohhot, ChinaBenzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon and a potent environmental pollutant, has been implicated in the dysregulation of lipid metabolism and metabolic diseases, warranting investigation into its effects on liver functions, particularly regarding fibroblast growth factor 21 (FGF21) mediated pathways. This study aimed to elucidate the effects of BaP on liver lipid metabolism and FGF21 expression via the aryl hydrocarbon receptor (AhR), with a focus on the regulatory interactions between BaP and xenobiotic response elements (XRE) within the promoter region of FGF21. Utilizing HepG2 cells, lipid accumulation was assessed through Oil Red O and Nile Red staining, while the expression of FGF21 protein was quantified by Western blotting and immunofluorescence techniques. Additionally, various truncated plasmids of the FGF21 promoter were synthesized for a dual-luciferase reporter assay to determine the relative luciferase activity and the modulation of FGF21 expression by BaP. The results revealed dose-dependent effects of BaP on lipid metabolism; specifically, low concentrations of BaP upregulated FGF21 expression by enhancing promoter activity in regions containing the XRE1 sequence, whereas higher BaP concentrations downregulated FGF21 expression via inhibition of promoter activity in regions with the XRE3 sequence. In conclusion, low doses of BaP facilitate AhR binding to XRE1, promoting FGF21 expression, while high doses disrupt this interaction through XRE3, culminating in decreased expression levels. These findings suggest a nuanced role of BaP in lipid metabolism regulation, with potential implications for understanding metabolic disorders associated with environmental pollutants. The study elucidates the relationship between AhR and FGF-21, providing an experimental basis for the search of new targets for the prevention and treatment of nonalcoholic fatty liver disease (NAFLD).https://www.frontiersin.org/articles/10.3389/fphar.2025.1595566/fullbenzo[a]pyrenfibroblast growth factor 21aryl hydrocarbon receptorxenobiotic response element 1xenobiotic response element 3hepatic lipid metabolism |
| spellingShingle | Mengdi Zhang Mengdi Zhang Xiaoli Lv Xiaoli Lv Chaojie Wang Chaojie Wang Lei Wang Lei Wang Han Wang Han Wang Xue Wang Xue Wang Yulu Du Yulu Du Jun Li Jun Li Jun Li Xiuli Han Xiuli Han Xiuli Han Lei Fan Lei Fan Yuxia Hu Yuxia Hu Yuxia Hu Tuya Bai Tuya Bai Weizhong Huangfu Fuhou Chang Fuhou Chang Molecular mechanisms of dose-dependent regulation of hepatic lipid metabolism by BaP through modulation of AhR binding to XRE1 or XRE3 Frontiers in Pharmacology benzo[a]pyren fibroblast growth factor 21 aryl hydrocarbon receptor xenobiotic response element 1 xenobiotic response element 3 hepatic lipid metabolism |
| title | Molecular mechanisms of dose-dependent regulation of hepatic lipid metabolism by BaP through modulation of AhR binding to XRE1 or XRE3 |
| title_full | Molecular mechanisms of dose-dependent regulation of hepatic lipid metabolism by BaP through modulation of AhR binding to XRE1 or XRE3 |
| title_fullStr | Molecular mechanisms of dose-dependent regulation of hepatic lipid metabolism by BaP through modulation of AhR binding to XRE1 or XRE3 |
| title_full_unstemmed | Molecular mechanisms of dose-dependent regulation of hepatic lipid metabolism by BaP through modulation of AhR binding to XRE1 or XRE3 |
| title_short | Molecular mechanisms of dose-dependent regulation of hepatic lipid metabolism by BaP through modulation of AhR binding to XRE1 or XRE3 |
| title_sort | molecular mechanisms of dose dependent regulation of hepatic lipid metabolism by bap through modulation of ahr binding to xre1 or xre3 |
| topic | benzo[a]pyren fibroblast growth factor 21 aryl hydrocarbon receptor xenobiotic response element 1 xenobiotic response element 3 hepatic lipid metabolism |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1595566/full |
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