Curcumin protects against high-fat diet-induced non-alcoholic simple fatty liver by inhibiting intestinal and hepatic NPC1L1 expression via down-regulation of SREBP-2/HNF1α pathway in hamsters.
Curcumin protects against high-fat diet-induced non-alcoholic simple fatty liver by inhibiting intestinal and hepatic NPC1L1 expression via down-regulation of SREBP-2/HNF1α pathway in hamsters.
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DOI：
10.1016/j.jnutbio.2023.109403
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发表时间：
2023-06
期刊：
影响因子：
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通讯作者：
Jie Yang;Jun Zou;Hai-yan Mai;Ting Hong;Hao Liu;Dan Feng
中科院分区：
文献类型：
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作者：
Jie Yang;Jun Zou;Hai-yan Mai;Ting Hong;Hao Liu;Dan Feng
NPC1L1介导胆固醇吸收，在非酒精性单纯性脂肪肝(NASFL)的发病机制中起关键作用。我们先前的研究表明，姜黄素降低了Caco-2细胞NPC1L1的表达和胆固醇的吸收。本研究旨在探讨姜黄素是否通过抑制固醇调节元件结合蛋白-2/肝细胞核因子1α途径抑制肠道和肝脏NPC1L1的表达，从而发挥抗非酒精性脂肪肝的作用。给6周龄仓鼠饲喂高脂饲料(HFD)，加或不加0.1%姜黄素，连续12周。补充姜黄素可降低血总胆固醇(TC)、甘油三酯(TG)和低密度脂蛋白胆固醇(LDLc)水平(20.2%、48.7%和36.5%)，降低肝脏TC和TG含量(26.1%和26.5%)。油红O染色显示，姜黄素可显著减轻高脂饲料所致大鼠肝脏脂肪堆积和肝脏脂肪变性，并伴有肠道和肝脏NPC1L1、SREBP-2和HNF1α表达降低(P<；0.05)，增加粪便中性固醇排泄量(114.5%)。此外，姜黄素还能降低Caco-2细胞和HepG2细胞对胆固醇的吸收(49.2%和52.7%)。姜黄素对NPC1L1表达和胆固醇吸收的抑制作用可通过阻断SREBP-2和HNF1α通路而被阻断。这些结果表明，姜黄素通过下调SREBP-2/HNF1α通路，抑制肠道和肝脏NPC1L1的表达，从而减少肠道胆固醇吸收和肝脏胆汁胆固醇重吸收，从而减轻肝脏胆固醇蓄积和脂肪变性，从而对高脂饲料诱导的非酒精性脂肪肝具有保护作用。我们的研究为姜黄素通过调节NPC1L1和胆固醇的肠-肝循环而成为治疗NASFL的潜在营养疗法提供了证据。
Niemann-pick C1-like 1 (NPC1L1) mediates cholesterol absorption and plays a key role in the pathogenesis of nonalcoholic simple fatty liver (NASFL). Our previous study showed that curcumin reduced NPC1L1 expression and cholesterol absorption in Caco-2 cells. This study aimed to investigate whether curcumin could inhibit intestinal and hepatic NPC1L1 expression through suppressing sterol regulatory element binding protein-2 (SREBP-2) / hepatocyte nuclear factor 1α (HNF1α) pathway, then exert anti-NASFL effects. Six-week hamsters were fed high-fat diet (HFD) with or without 0.1% curcumin for 12 weeks. Curcumin supplementation lowered blood total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol levels (20.2%, 48.7%, and 36.5%), and reduced liver TC and TG contents (26.1% and 26.5%). Oil Red O staining demonstrated that curcumin significantly alleviated HFD-induced liver fat accumulation and hepatic steatosis, which was accompanied by reduced intestinal and hepatic NPC1L1, SREBP-2 and HNF1α expression (P< .05) and increased fecal neutral sterol excretion (114.5%). Furthermore, curcumin decreased cholesterol absorption in Caco-2 cells and HepG2 cells (49.2 % and 52.7 %). The inhibitory effects of curcumin on NPC1L1 expression and cholesterol absorption could be prevented by blockade of the SREBP-2 and HNF1α pathway. These findings indicated that curcumin protected against HFD-induced NASFL by inhibiting intestinal and hepatic NPC1L1 expression via down-regulation of SREBP-2/HNF1α pathway, thus reducing intestinal cholesterol absorption and hepatic biliary cholesterol reabsorption, consequently alleviating liver cholesterol accumulation and steatosis. Our study provides evidence for curcumin as a potential nutritional therapy for NASFL by regulating NPC1L1 and enterohepatic circulation of cholesterol.