Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model
Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/17/9954 |
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| author | Eduardo E. Vargas-Pozada Erika Ramos-Tovar Juan D. Rodriguez-Callejas Irina Cardoso-Lezama Silvia Galindo-Gómez Daniel Talamás-Lara Verónica Rocío Vásquez-Garzón Jaime Arellanes-Robledo Víctor Tsutsumi Saúl Villa-Treviño Pablo Muriel |
| author_facet | Eduardo E. Vargas-Pozada Erika Ramos-Tovar Juan D. Rodriguez-Callejas Irina Cardoso-Lezama Silvia Galindo-Gómez Daniel Talamás-Lara Verónica Rocío Vásquez-Garzón Jaime Arellanes-Robledo Víctor Tsutsumi Saúl Villa-Treviño Pablo Muriel |
| author_sort | Eduardo E. Vargas-Pozada |
| collection | DOAJ |
| description | Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in a rat model of NASH. NASH was induced by feeding rats a high-fat, -sucrose, and -cholesterol diet (HFSCD) for 15 weeks along with a weekly low dose (400 mg/kg, i.p.) of CCl<sub>4</sub>. Caffeine was administered at 50 mg/kg p.o. The effects of HFSCD+CCl<sub>4</sub> and caffeine on the liver were evaluated using biochemical, ultrastructural, histological, and molecular biological approaches. The HFSCD+CCl<sub>4</sub>-treated rats showed fat accumulation in the liver, elevated levels of inflammatory mediators, NLRP3 inflammasome activation, antioxidant dysregulation, and liver fibrosis. Caffeine reduced necrosis, cholestasis, oxidative stress, and fibrosis. Caffeine exhibited anti-inflammatory effects by attenuating NLRP3 inflammasome activation. Moreover, caffeine prevented increases in toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) protein levels and mitigated the phosphorylation of mitogen-activated protein kinase (MAPK). Importantly, caffeine prevented the activation of hepatic stellate cells. This study is the first to report that caffeine ameliorates NASH by inhibiting NLRP3 inflammasome activation through the suppression of the TLR4/MAPK/NF-κB signaling pathway. |
| first_indexed | 2024-03-10T01:43:46Z |
| format | Article |
| id | doaj.art-eccd254dfa3c404f96c556d134d3b423 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:43:46Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-eccd254dfa3c404f96c556d134d3b4232023-11-23T13:20:22ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-012317995410.3390/ijms23179954Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH ModelEduardo E. Vargas-Pozada0Erika Ramos-Tovar1Juan D. Rodriguez-Callejas2Irina Cardoso-Lezama3Silvia Galindo-Gómez4Daniel Talamás-Lara5Verónica Rocío Vásquez-Garzón6Jaime Arellanes-Robledo7Víctor Tsutsumi8Saúl Villa-Treviño9Pablo Muriel10Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 07360, MexicoPostgraduate Studies and Research Section, School of Higher Education in Medicine-IPN, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Mexico City 11340, MexicoLaboratory of Neuroplasticity and Neurodegeneration, Department of Pharmacology, Cinvestav-IPN, Mexico City 07360, MexicoLaboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 07360, MexicoDepartment of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City 07360, MexicoDepartment of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City 07360, MexicoLaboratory of Fibrosis and Cancer, Faculty of Medicine and Surgery, ‘Benito Juárez’ Autonomous University of Oaxaca, UABJO, Oaxaca 68020, MexicoDirectorate of Catedras, National Council of Science and Technology CONACYT, Mexico City 03940, MexicoDepartment of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City 07360, MexicoDepartment of Cell Biology, Cinvestav-IPN, Mexico City 07360, MexicoLaboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 07360, MexicoCaffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in a rat model of NASH. NASH was induced by feeding rats a high-fat, -sucrose, and -cholesterol diet (HFSCD) for 15 weeks along with a weekly low dose (400 mg/kg, i.p.) of CCl<sub>4</sub>. Caffeine was administered at 50 mg/kg p.o. The effects of HFSCD+CCl<sub>4</sub> and caffeine on the liver were evaluated using biochemical, ultrastructural, histological, and molecular biological approaches. The HFSCD+CCl<sub>4</sub>-treated rats showed fat accumulation in the liver, elevated levels of inflammatory mediators, NLRP3 inflammasome activation, antioxidant dysregulation, and liver fibrosis. Caffeine reduced necrosis, cholestasis, oxidative stress, and fibrosis. Caffeine exhibited anti-inflammatory effects by attenuating NLRP3 inflammasome activation. Moreover, caffeine prevented increases in toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) protein levels and mitigated the phosphorylation of mitogen-activated protein kinase (MAPK). Importantly, caffeine prevented the activation of hepatic stellate cells. This study is the first to report that caffeine ameliorates NASH by inhibiting NLRP3 inflammasome activation through the suppression of the TLR4/MAPK/NF-κB signaling pathway.https://www.mdpi.com/1422-0067/23/17/9954caffeinenon-alcoholic steatohepatitisnucleotide-binding domainleucine-rich-containing familypyrin domain-containing-3 inflammasometoll-like receptor 4 |
| spellingShingle | Eduardo E. Vargas-Pozada Erika Ramos-Tovar Juan D. Rodriguez-Callejas Irina Cardoso-Lezama Silvia Galindo-Gómez Daniel Talamás-Lara Verónica Rocío Vásquez-Garzón Jaime Arellanes-Robledo Víctor Tsutsumi Saúl Villa-Treviño Pablo Muriel Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model International Journal of Molecular Sciences caffeine non-alcoholic steatohepatitis nucleotide-binding domain leucine-rich-containing family pyrin domain-containing-3 inflammasome toll-like receptor 4 |
| title | Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model |
| title_full | Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model |
| title_fullStr | Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model |
| title_full_unstemmed | Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model |
| title_short | Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model |
| title_sort | caffeine inhibits nlrp3 inflammasome activation by downregulating tlr4 mapk nf κb signaling pathway in an experimental nash model |
| topic | caffeine non-alcoholic steatohepatitis nucleotide-binding domain leucine-rich-containing family pyrin domain-containing-3 inflammasome toll-like receptor 4 |
| url | https://www.mdpi.com/1422-0067/23/17/9954 |
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