HWL-088, a new and highly effective FFA1/PPARδ dual agonist, attenuates nonalcoholic steatohepatitis by regulating lipid metabolism, inflammation and fibrosis
HWL-088, a new and highly effective FFA1/PPARδ dual agonist, attenuates nonalcoholic steatohepatitis by regulating lipid metabolism, inflammation and fibrosis
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HWL-088 是一种新型高效 FFA1/PPAR δ 双重激动剂，通过调节脂质代谢、炎症和纤维化来减轻非酒精性脂肪性肝炎
DOI：
10.1111/jphp.13342
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发表时间：
2020-07-31
影响因子：
3.3
通讯作者：
Wang, Guangji
中科院分区：
文献类型：
--
作者：
Hu, Lijun;Zhou, Zongtao;Wang, Guangji
目的非酒精性脂肪肝（NAFLD）是一种慢性进行性肝病，与高血糖、高血脂及氧化应激密切相关。据报道，游离脂肪酸受体1（FFA 1）激动剂可改善肝脏脂肪变性和纤维化，过氧化物酶体增殖物激活受体δ（PPAR δ）与FFA 1在能量代谢和纤维化中发挥协同作用。HWL-088是一种PPAR δ/FFA 1双重激动剂，其降糖作用优于代表性FFA 1激动剂TAK-875。然而，HWL-088保护NAFLD的能力尚不清楚。方法采用蛋氨酸和胆碱缺乏饮食（MCD）诱导的非酒精性脂肪性肝炎（NASH）模型，观察HWL-088对NAFLD的治疗作用。结果HWL-088对NAFLD的血糖控制、脂代谢和脂肪肝均有明显的改善作用。进一步的机制研究表明，HWL-088通过减少脂肪生成和增加脂肪分解来促进脂质代谢。结论HWL-088可能通过调节炎症、纤维化和氧化应激相关基因的表达水平来减轻NASH。
Objectives Nonalcoholic fatty liver (NAFLD), a chronic progressive liver disease, is highly correlated with pathoglycemia, dyslipidemia and oxidative stress. The free fatty acid receptor 1 (FFA1) agonists have been reported to improve liver steatosis and fibrosis, and the peroxisome proliferator-activated receptor delta (PPAR delta) plays a synergistic role with FFA1 in energy metabolism and fibrosis. HWL-088, a PPAR delta/FFA1 dual agonist, exerts better glucose-lowering effects than the representative FFA1 agonist TAK-875. However, the ability of HWL-088 to protect NAFLD was unknown. This study aimed to discover a new strategy for the treatment of NAFLD.Methods The methionine- and choline-deficient diet (MCD)-induced Nonalcoholic steatohepatitis (NASH) model was constructed to evaluate the effects of HWL-088.Key findings Administration of HWL-088 exerted multiple benefits on glucose control, lipid metabolism and fatty liver. Further mechanism research indicated that HWL-088 promotes lipid metabolism by decreasing lipogenesis and increasing lipolysis. Moreover, HWL-088 attenuates NASH by regulating the expression levels of genes related to inflammation, fibrosis and oxidative stress.Conclusions These positive results indicated that PPAR delta/FFA1 dual agonist HWL-088 might be a potential candidate to improve multiple pathogenesis of NASH.