Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury.
Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury.
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DOI：
10.1038/s41598-021-83144-w
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发表时间：
2021-03-04
影响因子：
4.6
通讯作者：
Nomura M
中科院分区：
文献类型：
--
作者：
Hasuzawa N;Tatsushima K;Wang L;Kabashima M;Tokubuchi R;Nagayama A;Ashida K;Ogawa Y;Moriyama Y;Nomura M
囊泡核苷酸转运体（VNUT）负责各种ATP分泌细胞的囊泡储存和释放ATP，并在嘌呤能信号传导中发挥重要作用。虽然已知细胞外ATP及其降解产物可通过嘌呤受体介导各种炎症反应，但水疱性ATP释放是否影响脂肪性肝炎和急性肝损伤尚不清楚。在本研究中，我们研究了氯膦酸钠（一种有效的选择性VNUT抑制剂）对小鼠急性和慢性肝脏炎症的影响。在蛋氨酸/胆碱缺乏饮食诱导的非酒精性脂肪性肝炎（NASH）模型中，氯膦酸钠的使用减少了肝脏炎症、纤维化和甘油三酯的积累。氯膦酸钠还能保护小鼠免受高脂肪/高胆固醇饮食引起的脂肪性肝炎。此外，氯膦酸钠通过减少炎症因子和肝细胞凋亡来预防d-半乳糖胺和脂多糖诱导的急性肝损伤。在体外实验中，氯膦酸盐抑制葡萄糖诱导的VNUT介导的水泡ATP释放，降低离体肝细胞内甘油三酯的分泌水平和水平。这些结果表明，vnut依赖的水疱ATP释放在免疫细胞的募集、细胞因子的产生和肝脏脂肪变性的加重中起着至关重要的作用。药理抑制VNUT可能对肝脏炎症性疾病（包括NASH和急性毒性损伤）提供治疗益处。
The vesicular nucleotide transporter (VNUT) is responsible for the vesicular storage and release of ATP from various ATP-secreting cells, and it plays an essential role in purinergic signaling. Although extracellular ATP and its degradation products are known to mediate various inflammatory responses via purinoceptors, whether vesicular ATP release affects steatohepatitis and acute liver injury is far less understood. In the present study, we investigated the effects of clodronate, a potent and selective VNUT inhibitor, on acute and chronic liver inflammation in mice. In a model of methionine/choline-deficient diet-induced non-alcoholic steatohepatitis (NASH), the administration of clodronate reduced hepatic inflammation, fibrosis, and triglyceride accumulation. Clodronate also protected mice against high-fat/high-cholesterol diet-induced steatohepatitis. Moreover, prophylactic administration of clodronate prevented d-galactosamine and lipopolysaccharide-induced acute liver injury by reducing inflammatory cytokines and hepatocellular apoptosis. In vitro, clodronate inhibited glucose-induced vesicular ATP release mediated by VNUT and reduced the intracellular level and secretion of triglycerides in isolated hepatocytes. These results suggest that VNUT-dependent vesicular ATP release plays a crucial role in the recruitment of immune cells, cytokine production, and the aggravation of steatosis in the liver. Pharmacological inhibition of VNUT may provide therapeutic benefits in liver inflammatory disorders, including NASH and acute toxin-induced injury.
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影响因子：
3.7
作者：
Mihara H;Uchida K;Koizumi S;Moriyama Y
通讯作者：
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影响因子：
2.8
作者：
Han, Chunchun;Wang, Jiwen;Pan, Zhixiong
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影响因子：
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通讯作者：
Tominaga M
影响因子：
9.8
作者：
Buzzetti, Elena;Pinzani, Massimo;Tsochatzis, Emmanuel A.
通讯作者：
Tsochatzis, Emmanuel A.
DOI：
10.1152/ajpgi.00352.2011
发表时间：
2012-05-01
影响因子：
4.5
作者：
Hoque, Rafaz;Sohail, Muhammed Adnan;Mehal, Wajahat Z.
通讯作者：
Mehal, Wajahat Z.