KLF10 promotes nonalcoholic steatohepatitis progression through transcriptional activation of zDHHC7

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.

Examining the Pathogenesis of MAFLD and the Medicinal Properties of Natural Products from a Metabolic Perspective

“…After palmitoylation, CD36 is able to recognize and capture fatty acids, followed by depalmitoylation to initiate endocytosis to transport fatty acids into cells [17]. CD36 localization to the plasma membrane increases in the steatohepatitis phase, and the inhibition of CD36 palmitoylation promotes its translocation to the mitochondria, thereby ameliorating hepatic lipid metabolism disorders in mice and reducing inflammatory responses [18,19]. Therefore, CD36 could be a crucial and promising therapeutic target for MAFLD.…”

Machine learning-based integration identifies ferroptosis hub genes in nonalcoholic steatohepatitis

“…4H and 4I). We conducted a thorough search on the PubMed website to identify nine pertinent articles related to NASH [23][24][25][26][27][28][29][30][31]. From these articles, we meticulously extracted a total of 43 essential genes directly associated with NASH.…”

Krüppel-like Factor 10 as a Prognostic and Predictive Biomarker of Radiotherapy in Pancreatic Adenocarcinoma

“…As a circadian-clock-controlled transcription factor, KLF10 suppresses lipogenic genes of glucose and lipid metabolism in the liver and it affects gluconeogenesis, contributing to diabetes [50,51]. KLF10 alleviates hepatic steatosis and nonalcoholicsteatohepatitis by downregulating SREBP-1c involving lipogenesis [52,53]. KLF10-deficient mice exhibit reduced receptor activator of nuclear factor kappa-B ligand, increased osteoprotegerin, and delayed8 osteoclast differentiation which led to reduced bone turnover and osteopenia [49,51,54].…”

“…KLF10 expression in various cancer tissues has been reported to be significantly lower than that in normal tissues [63,71]. In PDAC, KLF10 expression was low in two thirds of patients and was inversely correlated with the cancer stage [36,53]. Despite alterations in the TGF-β signaling pathway components in patients with PDAC, KLF 10 could regulate TGF-β signaling and inhibit epithelial cell proliferation in pancreatic cancer cells [72].…”