Silencing of STE20-type kinase MST3 in mice with antisense oligonucleotide treatment ameliorates diet-induced nonalcoholic fatty liver disease
Silencing of STE20-type kinase MST3 in mice with antisense oligonucleotide treatment ameliorates diet-induced nonalcoholic fatty liver disease
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DOI：
10.1096/fj.202002671rr
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发表时间：
2021-05-01
期刊：
影响因子：
4.8
通讯作者：
Mahlapuu, Margit
中科院分区：
文献类型：
--
作者：
Caputo, Mara;Kurhe, Yeshwant;Mahlapuu, Margit
非酒精性脂肪性肝病（NAFLD）正在成为世界范围内慢性肝病的主要原因。尽管在该领域进行了大量的非临床和临床研究，但目前尚未批准治疗NAFLD的特定药物治疗方法，这已被认为是21世纪未满足的主要医疗需求之一。我们最近的研究发现ste20型激酶MST3定位于细胞内脂滴，是人肝细胞异位脂肪积累的关键调节因子。在这里，我们探讨了mst3靶向反义寡核苷酸（ASOs）治疗是否可以促进肝脏脂质清除并减轻肥胖小鼠NAFLD的进展。我们发现，在小鼠中施用靶向mst3的ASOs可有效改善高脂肪饮食诱导的NAFLD，包括肝脂肪变性、炎症、纤维化和肝细胞损伤。在机制上，Mst3 ASOs抑制脂肪生成基因表达以及乙酰辅酶a羧化酶（ACC）蛋白丰度，并显著降低肥胖小鼠肝脏中脂肪毒性介导的氧化应激和内质网应激。此外，我们发现MST3蛋白水平与人类肝脏活检中NAFLD的严重程度呈正相关。总之，本研究提供了第一个体内证据，证明在饮食燃料过剩的情况下，拮抗MST3信号足以缓解NAFLD的进展，值得未来的研究来评估MST3抑制剂是否可以为NAFLD患者的治疗提供新的策略。
Nonalcoholic fatty liver disease (NAFLD) is emerging as a leading cause of chronic liver disease worldwide. Despite intensive nonclinical and clinical research in this field, no specific pharmacological therapy is currently approved to treat NAFLD, which has been recognized as one of the major unmet medical needs of the 21st century. Our recent studies have identified STE20-type kinase MST3, which localizes to intracellular lipid droplets, as a critical regulator of ectopic fat accumulation in human hepatocytes. Here, we explored whether treatment with Mst3-targeting antisense oligonucleotides (ASOs) can promote hepatic lipid clearance and mitigate NAFLD progression in mice in the context of obesity. We found that administration of Mst3-targeting ASOs in mice effectively ameliorated the full spectrum of high-fat diet-induced NAFLD including liver steatosis, inflammation, fibrosis, and hepatocellular damage. Mechanistically, Mst3 ASOs suppressed lipogenic gene expression, as well as acetyl-CoA carboxylase (ACC) protein abundance, and substantially reduced lipotoxicity-mediated oxidative and endoplasmic reticulum stress in the livers of obese mice. Furthermore, we found that MST3 protein levels correlated positively with the severity of NAFLD in human liver biopsies. In summary, this study provides the first in vivo evidence that antagonizing MST3 signaling is sufficient to mitigate NAFLD progression in conditions of excess dietary fuels and warrants future investigations to assess whether MST3 inhibitors may provide a new strategy for the treatment of patients with NAFLD.