KLF10 promotes nonalcoholic steatohepatitis progression through transcriptional activation of zDHHC7 [KFL10 overexpression]

Nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis, inflammation, and liver injury, has become a leading cause of end-stage liver diseases and liver transplantation. Krüppel-like factors 10 (KLF10) is a Cys2/His2 zinc finger transcription factor that regulates cell growth, apoptosis, and differentiation. However, whether it plays a role in the development and progression of chronic liver diseases like NASH remains poorly understood. In the present study, we found that KLF10 expression was selectively upregulated in the mouse models and human patients with NASH, compared with simple steatosis (NAFL). Gain- and loss-of function studies demonstrated that hepatocyte-specific overexpression of KLF10 aggravated, whereas its depletion alleviated diet-induced NASH pathogenesis in mice. Mechanistically, transcriptomic analysis and subsequent functional experiments showed that KLF10 promotes hepatic lipid accumulation and inflammation through the palmitoylation and plasma membrane localization of fatty acid translocase CD36 via transcriptionally activation of zDHHC7. Indeed, both expression of zDHHC7 and palmitoylation of CD36 are required for the pathogenic roles of KLF10 in NASH progression. Thus, our results identify an important role for KLF10 in NAFL-to-NASH development through zDHHC7-mediated CD36 palmitoylation. primary hepatocyte transfected with lentivirus expressing negative control or KLF10

非酒精性脂肪性肝炎（Nonalcoholic steatohepatitis, NASH）以肝脂肪变、炎症及肝损伤为特征，现已成为终末期肝病与肝移植的首要诱因。Krüppel样因子10（Krüppel-like factors 10, KLF10）是一类Cys2/His2型锌指转录因子，可调控细胞增殖、凋亡与分化。然而，其在NASH等慢性肝病的发生发展中是否发挥作用，目前仍不甚明确。本研究发现，与单纯性脂肪变性（NAFL）模型相比，KLF10在NASH小鼠模型及人类患者体内的表达呈选择性上调。功能获得与功能缺失实验证实，肝细胞特异性过表达KLF10会加重小鼠饮食诱导的NASH发病进程，而沉默KLF10则可缓解该病症。机制层面，转录组分析与后续功能实验显示，KLF10通过转录激活zDHHC7，介导脂肪酸转位酶CD36的棕榈酰化及其质膜定位，进而促进肝内脂质蓄积与炎症反应。进一步验证表明，zDHHC7的表达与CD36的棕榈酰化均为KLF10在NASH进展中发挥致病作用所必需。综上，本研究结果揭示了KLF10通过zDHHC7介导的CD36棕榈酰化，在NAFL向NASH的转化进程中发挥重要调控作用。转染了表达阴性对照或KLF10的慢病毒的原代肝细胞。