Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai, China.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Geriatrics, National Key Clinic Specialty, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
Transl Res. 2020 Aug;222:28-40. doi: 10.1016/j.trsl.2020.04.011. Epub 2020 May 11.
Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease characterized by fat accumulation and inflammation in liver. Yet, the mechanistic insight and diagnostic and therapeutic options of NASH remain incompletely understood. This study tested the roles of cysteine protease cathepsin B (CatB) in mouse NASH development. Immunoblot revealed increased liver CatB expression in NASH mice. Fructose-palmitate-cholesterol diet increased body weight gain, liver to body weight ratio, blood fasting glucose, plasma total cholesterol and alanine transaminase levels, and liver triglyceride, but decreased plasma high-density lipoprotein in wild-type mice. All these changes were blunted in CatB-deficient (Ctsb) mice. In parallel to reduced expression of genes involved in liver lipid transport and lipogenesis, liver CD36, FABP4, and PPARγ protein levels were also significantly decreased in Ctsb mice, although CatB deficiency did not affect liver gluconeogenesis and fatty acid beta-oxidation-associated gene expression. Mechanistic studies showed that CatB deficiency decreased liver expression of adhesion molecules, inflammatory cytokine, and chemokine, along with reduced liver inflammatory cell infiltration. CatB deficiency also promoted M2 macrophage polarization and reduced liver TGF-β1 signaling and fibrosis. Together, CatB deficiency improves liver function in NASH mice by suppressing de novo lipogenesis and liver inflammation and fibrosis.
非酒精性脂肪性肝炎（NASH）是一种严重的非酒精性脂肪肝疾病，其特征是肝脏脂肪堆积和炎症。然而，NASH 的发病机制、诊断和治疗选择仍不完全清楚。本研究测试了半胱氨酸蛋白酶组织蛋白酶 B（CatB）在小鼠 NASH 发展中的作用。免疫印迹显示 NASH 小鼠肝脏 CatB 表达增加。果糖-棕榈酸-胆固醇饮食增加了野生型小鼠的体重增加、肝重/体重比、空腹血糖、血浆总胆固醇和丙氨酸转氨酶水平，以及肝甘油三酯，但降低了血浆高密度脂蛋白。所有这些变化在 CatB 缺陷（Ctsb）小鼠中都被减弱。与参与肝脏脂质转运和脂肪生成的基因表达降低平行的是，CatB 缺陷小鼠肝脏 CD36、FABP4 和 PPARγ 蛋白水平也显著降低，尽管 CatB 缺乏不影响肝脏糖异生和脂肪酸β氧化相关基因的表达。机制研究表明，CatB 缺乏减少了肝脏黏附分子、炎症细胞因子和趋化因子的表达，同时减少了肝脏炎症细胞浸润。CatB 缺乏还促进了 M2 巨噬细胞极化，减少了肝 TGF-β1 信号和纤维化。总之，CatB 缺乏通过抑制从头脂肪生成和肝脏炎症和纤维化来改善 NASH 小鼠的肝功能。
