Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
Arch Biochem Biophys. 2021 Jul 15;705:108894. doi: 10.1016/j.abb.2021.108894. Epub 2021 May 6.
Accumulating evidence suggests that vitamin D (VD) has a therapeutic effect on non-alcoholic fatty liver disease (NAFLD). Pyroptosis and gut microbiota have been recognized as critical factors of the progression of NAFLD. However, the effect of VD on the pyroptosis and gut microbiota in NAFLD remains inconclusive. Herein, rats were fed high fat diet (HFD) for 12 weeks and concurrently treated with 5 μg/kg 1,25(OH)D twice a week. BRL-3A cells were stimulated with 0.4 mmol/L palmitic acid (PA) and 1 μg/ml lipopolysaccharide (LPS) for 16 h and treated with 10 mol/L 1,25(OH)D. Effect of VD on the hepatic injury, lipid accumulation, activation of NLRP3 inflammasome and pyroptosis was determined in vivo and in vitro. Next, gasdermin D N-terminal (GSDMD-N) fragment was overexpressed in BRL-3A cells to investigate the role of pyroptosis in the therapeutic effect of VD on NAFLD. In addition, gut microbiota in NAFLD rats was also analyzed. Results showed that VD attenuated HFD-induced hepatic injury in vivo and PA-LPS-induced impairment of cell viability in vitro, and inhibited lipid accumulation, activation of NLRP3 inflammasome and pyroptosis in vivo and in vitro. GSDMD-N fragment overexpression suppressed the protective effect of VD on PA-LPS-induced activation of NLRP3 inflammasome, impairment of cell viability and lipid accumulation, indicating that VD might attenuate NAFLD through inhibiting pyroptosis. Additionally, VD also restored HFD-induced gut microbiota dysbiosis by increasing the relative abundance of Lactobacillus and reducing that of Acetatifactor, Oscillibacter and Flavonifractor. This study provides a novel mechanism underlying VD therapy against NAFLD.
越来越多的证据表明维生素 D（VD）对非酒精性脂肪性肝病（NAFLD）具有治疗作用。细胞焦亡和肠道微生物群已被认为是 NAFLD 进展的关键因素。然而，VD 对 NAFLD 中细胞焦亡和肠道微生物群的影响仍存在争议。在此，我们使用高脂肪饮食（HFD）喂养大鼠 12 周，并同时每周两次给予 5μg/kg 1,25(OH)2D 治疗。使用 0.4mmol/L 棕榈酸（PA）和 1μg/ml 脂多糖（LPS）刺激 BRL-3A 细胞 16h，并使用 10μmol/L 1,25(OH)2D 处理。在体内和体外研究 VD 对肝损伤、脂质积累、NLRP3 炎性体激活和细胞焦亡的影响。接下来，在 BRL-3A 细胞中转染 GSDMD-N 片段，以研究细胞焦亡在 VD 治疗 NAFLD 中的作用。此外，还分析了 NAFLD 大鼠的肠道微生物群。结果表明，VD 减轻了体内 HFD 诱导的肝损伤和体外 PA-LPS 诱导的细胞活力损伤，并抑制了体内和体外的脂质积累、NLRP3 炎性体激活和细胞焦亡。GSDMD-N 片段过表达抑制了 VD 对 PA-LPS 诱导的 NLRP3 炎性体激活、细胞活力损伤和脂质积累的保护作用，表明 VD 可能通过抑制细胞焦亡来减轻 NAFLD。此外，VD 还通过增加乳杆菌的相对丰度和降低拟杆菌属、阿克曼氏菌属和黄杆菌属的相对丰度来恢复 HFD 诱导的肠道微生物群失调。本研究为 VD 治疗 NAFLD 的机制提供了新的见解。
