KLF10 promotes nonalcoholic steatohepatitis progression through transcriptional activation of zDHHC7. (2nd May 2022)

• Record Type: Journal Article
• Authors: Yang, Shu; Jia, Lijing; Xiang, Jiaqing; Yang, Guangyan; Qiu, Shanhu; Kang, Lin; Zheng, Peilin; Liang, Zhen; Lu, Yan
• Is Part Of: EMBO reports. Volume 23:Number 6(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-05-02
• Subjects: CD36 -- KLF10 -- nonalcoholic steatohepatitis -- palmitoylation -- zDHHC7; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202154229
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: 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 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 development. Thus, our results identify an important role for KLF10 in NAFL‐to‐NASH progression through zDHHC7‐mediated CD36 palmitoylation. Synopsis: KLF10 enhances hepatic lipid accumulation, inflammation, and fibrosis by transcriptionally upregulating zDHHC7, which promotes palmitoylation and plasma membrane localization of CD36 in hepatocytes. KLF10 is selectively increased in mouse models and human patients with nonalcoholic steatohepatitis (NASH). Hepatic KLF10 overexpression aggravates liver inflammation and lipid accumulation in mice. Hepatocyte‐specific KLF10 knockout mice are protected from diet‐induced NASH progression. KLF10‐mediated transcriptional activation of zDHHC7 facilitates CD36 palmitoylation to promote NASH progression. Abstract : KLF10 enhances hepatic lipid accumulation, inflammation, and fibrosis by transcriptionally upregulating zDHHC7, which promotes palmitoylation and plasma membrane localization of CD36 in hepatocytes.