Vesicular ATP release from hepatocytes plays a role in the progression of nonalcoholic steatohepatitis
Vesicular ATP release from hepatocytes plays a role in the progression of nonalcoholic steatohepatitis
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DOI：
10.1016/j.bbadis.2020.166013
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发表时间：
2021-01-23
影响因子：
6.2
通讯作者：
Nomura, Masatoshi
中科院分区：
文献类型：
--
作者：
Tatsushima, Keita;Hasuzawa, Nao;Nomura, Masatoshi
随着世界范围内代谢综合征的增加，非酒精性脂肪性肝炎(NASH)正成为一个日益严重的公共卫生问题。已知细胞外核苷酸在许多炎症性疾病中通过启动嘌呤能信号作为危险信号，尽管嘌呤能信号在NASH进展中的作用仍有待阐明。囊泡核苷酸转运体(VNUT)是囊泡释放ATP启动嘌呤能信号转运蛋白的关键分子。在这里，我们研究了VNUT在非酒精性脂肪性肝炎进展中的作用。VNUT在小鼠肝细胞中表达，并至少部分与含载脂蛋白B(ApoB)的囊泡相关。高糖刺激可引起肝细胞释放相当数量的三磷酸腺苷，但在Vnut基因敲除(-/-)小鼠的肝细胞中则消失。葡萄糖处理还刺激肝细胞分泌甘油三酯，这种作用可被P2Y受体拮抗剂PPADS和MRS211以及VNUT抑制剂氯屈膦酸盐抑制，并且在Vut(-/-)小鼠中显著减少。在体内，观察到餐后肝细胞分泌甘油三酯，而血清甘油三酯水平显著降低(-/-)小鼠。在高脂饮食下，野生型小鼠的肝脏表现出严重的炎症、纤维化和巨噬细胞浸润，这与人类的NASH相似，而这种NASH病理在Vnut(-/-)小鼠中没有观察到。这些结果表明，VNUT介导的囊泡性ATP释放调节甘油三酯的分泌，并参与肝细胞的慢性炎症。由于阻断囊泡性ATP的释放可以防止脂肪性肝炎的进展，VNUT可能是NASH的一个药理靶点。
Non-alcoholic steatohepatitis (NASH) is becoming a growing public health problem along with the increase of metabolic syndrome worldwide. Extracellular nucleotides are known to serve as a danger signal by initiating purinergic signaling in many inflammatory disorders, although the role of purinergic signaling in the progression of NASH remains to be clarified. Vesicular nucleotide transporter (VNUT) is a key molecule responsible for vesicular ATP release to initiate purinergic signaling. Here, we studied the role of VNUT in the progression of nonalcoholic steatohepatitis. VNUT was expressed in mouse hepatocytes and associated, at least in part, with apolipoprotein B (apoB)-containing vesicles. High glucose stimulation evoked release of appreciable amount of ATP from hepatocytes, which disappeared in hepatocytes of Vnut knockout (Vnut(-/-)) mice. Glucose treatment also stimulated triglyceride secretion from hepatocytes, which was inhibited by PPADS and MRS211, antagonists of P2Y receptors, and clodronate, a VNUT inhibitor, and was significantly reduced in Vnut(-/-) mice. In vivo, postprandial secretion of triglyceride from hepatocytes was observed, while the serum triglyceride level was significantly reduced in Vnut(-/-) mice. On a high-fat diet, the liver of wild type mice exhibited severe inflammation, fibrosis, and macrophage infiltration, which is similar to NASH in humans, while this NASH pathology was not observed in Vnut(-/-) mice. These results suggest that VNUT-mediated vesicular ATP release regulates triglyceride secretion and involves in chronic inflammation in hepatocytes. Since blockade of vesicular ATP release protects against progression of steatohepatitis, VNUT may be a pharmacological target for NASH.