Wang Wei, Wang Chuang, Ding Xiao-Qin, Pan Ying, Gu Ting-Ting, Wang Ming-Xing, Liu Yang-Liu, Wang Fu-Meng, Wang Shui-Juan, Kong Ling-Dong
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
Br J Pharmacol. 2013 Jul;169(6):1352-71. doi: 10.1111/bph.12226.
Thioredoxin-interacting protein (TXNIP), a regulator of cellular oxidative stress, has been associated with activation of NOD-like receptor 3 (NLRP3) inflammasome, inflammation and lipid metabolism, suggesting it has a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) in diabetes. In this study we investigated whether TXNIP is involved in type 1 diabetes-associated NAFLD and whether antioxidants, quercetin and allopurinol, alleviate NAFLD by targeting TXNIP.
Diabetes was induced in male Sprague-Dawley rats by a single i.p. injection of 55 mg · kg⁻¹ streptozotocin. Quercetin and allopurinol were given p.o. to diabetic rats for 7 weeks. Hepatic function, oxidative stress, inflammation and lipid levels were determined. Rat BRL-3A and human HepG2 cells were exposed to high glucose (30 mM) in the presence and absence of antioxidants, TXNIP siRNA transfection or caspase-1 inhibitor, Ac-YVAD-CMK.
Quercetin and allopurinol significantly inhibited the TXNIP overexpression, activation of NLRP3 inflammasome, down-regulation of PPARα and up-regulation of sterol regulatory element binding protein-1c (SREBP-1c), SREBP-2, fatty acid synthase and liver X receptor α, as well as elevation of ROS and IL-1β in diabetic rat liver. These effects were confirmed in hepatocytes in vitro and it was further shown that TXNIP down-regulation contributed to the suppression of NLRP3 inflammasome activation, inflammation and changes in PPARα and SREBPs.
Inhibition of hepatic TXNIP by quercetin and allopurinol contributes to the reduction in liver inflammation and lipid accumulation under hyperglycaemic conditions. The targeting of hepatic TXNIP by quercetin and allopurinol may have therapeutic implications for prevention of type 1 diabetes-associated NAFLD.
硫氧还蛋白相互作用蛋白（TXNIP）是细胞氧化应激的调节因子，与NOD样受体3（NLRP3）炎性小体的激活、炎症及脂质代谢相关，提示其在糖尿病非酒精性脂肪性肝病（NAFLD）的发病机制中起作用。在本研究中，我们调查了TXNIP是否参与1型糖尿病相关的NAFLD，以及抗氧化剂槲皮素和别嘌醇是否通过靶向TXNIP减轻NAFLD。
通过腹腔注射55 mg·kg⁻¹链脲佐菌素诱导雄性Sprague-Dawley大鼠患糖尿病。将槲皮素和别嘌醇经口给予糖尿病大鼠7周。测定肝功能、氧化应激、炎症和脂质水平。在有或没有抗氧化剂、TXNIP小干扰RNA转染或半胱天冬酶-1抑制剂Ac-YVAD-CMK的情况下，将大鼠BRL-3A和人HepG2细胞暴露于高糖（30 mM）环境中。
槲皮素和别嘌醇显著抑制糖尿病大鼠肝脏中TXNIP的过表达、NLRP3炎性小体的激活、过氧化物酶体增殖物激活受体α（PPARα）的下调以及固醇调节元件结合蛋白-1c（SREBP-1c）、SREBP-2、脂肪酸合酶和肝脏X受体α的上调，以及活性氧（ROS）和白细胞介素-1β（IL-1β）的升高。这些作用在体外肝细胞中得到证实，并且进一步表明TXNIP的下调有助于抑制NLRP3炎性小体的激活以及炎症和PPARα及SREBPs的变化。
槲皮素和别嘌醇对肝脏TXNIP的抑制作用有助于在高血糖条件下减少肝脏炎症和脂质蓄积。槲皮素和别嘌醇对肝脏TXNIP的靶向作用可能对预防1型糖尿病相关的NAFLD具有治疗意义。
