Departments of Molecular Genetics, Human Biology and Surgery, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, 6229 ER, Maastricht, The Netherlands.
Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria.
Sci Rep. 2017 Jun 14;7(1):3494. doi: 10.1038/s41598-017-03796-5.
Due to the obesity epidemic, non-alcoholic steatohepatitis (NASH) is a prevalent liver disease, characterized by fat accumulation and inflammation of the liver. However, due to a lack of mechanistic insight, diagnostic and therapeutic options for NASH are poor. Recent evidence has indicated cathepsin D (CTSD), a lysosomal enzyme, as a marker for NASH. Here, we investigated the function of CTSD in NASH by using an in vivo and in vitro model. In addition to diminished hepatic inflammation, inhibition of CTSD activity dramatically improved lipid metabolism, as demonstrated by decreased plasma and liver levels of both cholesterol and triglycerides. Mechanistically, CTSD inhibition resulted in an increased conversion of cholesterol into bile acids and an elevated excretion of bile acids via the feces, indicating that CTSD influences lipid metabolism. Consistent with these findings, treating Wt BMDMs with PepA in vitro showed a similar decrease in inflammation and an analogous effect on cholesterol metabolism.
CTSD is a key player in the development of hepatic inflammation and dyslipidemia. Therefore, aiming at the inhibition of the activity of CTSD may lead to novel treatments to combat NASH.
由于肥胖症的流行，非酒精性脂肪性肝炎（NASH）是一种常见的肝脏疾病，其特征是肝脏脂肪堆积和炎症。然而，由于缺乏对发病机制的深入了解，目前用于 NASH 的诊断和治疗方法仍很有限。最近的证据表明，组织蛋白酶 D（CTSD）作为 NASH 的标志物，是溶酶体中的一种酶。在这里，我们通过体内和体外模型研究了 CTSD 在 NASH 中的功能。除了肝脏炎症减轻外，抑制 CTSD 活性还显著改善了脂质代谢，表现为血浆和肝脏中胆固醇和甘油三酯水平降低。从机制上讲，CTSD 抑制导致胆固醇转化为胆汁酸，并通过粪便增加胆汁酸的排泄，表明 CTSD 影响脂质代谢。与这些发现一致的是，用 PepA 在体外处理 Wt BMDMs 显示出炎症减少和胆固醇代谢的类似作用。
CTSD 是肝炎症和血脂异常发展的关键因素。因此，针对 CTSD 活性的抑制可能会为治疗 NASH 提供新的治疗方法。
