The phytochemical polydatin ameliorates non-alcoholic steatohepatitis by restoring lysosomal function and autophagic flux
The phytochemical polydatin ameliorates non-alcoholic steatohepatitis by restoring lysosomal function and autophagic flux
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植物化学虎杖甙通过恢复溶酶体功能和自噬通量来改善非酒精性脂肪性肝炎
DOI：
10.1111/jcmm.14320
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发表时间：
2019-06-01
影响因子：
5.3
通讯作者：
Wu, William K. K.
中科院分区：
文献类型：
--
作者：
Chen, Xiaoting;Chan, Hung;Wu, William K. K.
细胞内脂质的自噬降解受损与非酒精性脂肪性肝炎（NASH）的发生有因果关系。因此，可以恢复肝脏自噬通量的药物可能对这种日益流行的疾病具有治疗潜力。在此，我们研究了白藜芦醇的天然前体虎杖苷在NASH的小鼠营养模型和脂肪变性的细胞系模型中的作用。结果表明，口服白藜芦醇苷可保护喂食蛋氨酸胆碱缺乏饮食的db/db小鼠的肝脏脂质蓄积，减轻炎症和肝细胞损伤。白藜芦醇苷也减轻软脂酸诱导的肝细胞脂质蓄积。在这两种模型中，虎杖苷恢复了NASH或脂肪变性损害的溶酶体功能和自噬通量。在机制上，虎杖苷抑制mTOR信号传导并上调TFEB的表达和活性，TFEB是溶酶体功能的已知主调节剂。总之，白藜芦醇苷通过恢复自噬流来改善NASH。Polydatin调节的自噬与TFEB抑制mTOR通路和恢复溶酶体功能有关。我们的研究提供了肯定的临床前证据，为未来的临床试验提供信息，以检查虎杖苷在人体中的潜在抗NASH作用。
Impaired autophagic degradation of intracellular lipids is causally linked to the development of non-alcoholic steatohepatitis (NASH). Pharmacological agents that can restore hepatic autophagic flux could therefore have therapeutic potentials for this increasingly prevalent disease. Herein, we investigated the effects of polydatin, a natural precursor of resveratrol, in a murine nutritional model of NASH and a cell line model of steatosis. Results showed that oral administration of polydatin protected against hepatic lipid accumulation and alleviated inflammation and hepatocyte damage in db/db mice fed methionine-choline deficient diet. Polydatin also alleviated palmitic acid-induced lipid accumulation in cultured hepatocytes. In both models, polydatin restored lysosomal function and autophagic flux that were impaired by NASH or steatosis. Mechanistically, polydatin inhibited mTOR signalling and up-regulated the expression and activity of TFEB, a known master regulator of lysosomal function. In conclusion, polydatin ameliorated NASH through restoring autophagic flux. The polydatin-regulated autophagy was associated with inhibition of mTOR pathway and restoration of lysosomal function by TFEB. Our study provided affirmative preclinical evidence to inform future clinical trials for examining the potential anti-NASH effect of polydatin in humans.