Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 07360, Mexico.
Postgraduate 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, Mexico.
Int J Mol Sci. 2022 Sep 1;23(17):9954. doi: 10.3390/ijms23179954.
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. Caffeine was administered at 50 mg/kg p.o. The effects of HFSCD+CCl and caffeine on the liver were evaluated using biochemical, ultrastructural, histological, and molecular biological approaches. The HFSCD+CCl-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.
咖啡因对非酒精性脂肪性肝炎（NASH）等肝脏疾病具有保护作用；然而，其涉及吡喃结构域包含蛋白 3（NLRP3）炎性小体信号通路的作用机制仍有待阐明。本研究旨在评估咖啡因对 NASH 大鼠模型中 NLRP3 炎性小体信号通路的影响。NASH 通过给大鼠喂食高脂肪、高蔗糖和高胆固醇饮食（HFSCD）15 周，并每周给予低剂量（400mg/kg，腹腔注射）的 CCl 诱导。咖啡因以 50mg/kg 灌胃给药。采用生化、超微结构、组织学和分子生物学方法评估 HFSCD+CCl 和咖啡因对肝脏的影响。HFSCD+CCl 处理的大鼠肝脏出现脂肪堆积，炎症介质水平升高，NLRP3 炎性小体激活，抗氧化失调和肝纤维化。咖啡因减少了坏死、胆汁淤积、氧化应激和纤维化。咖啡因通过减弱 NLRP3 炎性小体的激活发挥抗炎作用。此外，咖啡因可防止 Toll 样受体 4（TLR4）和核因子-κB（NF-κB）蛋白水平升高，并减轻丝裂原活化蛋白激酶（MAPK）的磷酸化。重要的是，咖啡因可阻止肝星状细胞的激活。本研究首次报道，咖啡因通过抑制 TLR4/MAPK/NF-κB 信号通路抑制 NLRP3 炎性小体的激活，从而改善 NASH。
