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Published on: March 24, 2015
C/EBPβ-VCAM1 axis in Kupffer cells promotes hepatic inflammation in MASLD
Shuang-Zhe Lin1, Yang Xie1, Yu-Qing Cheng1
1Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background & Aims:
Kupffer cells (KCs) can promote hepatic inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying molecular mechanisms are not fully understood. C/EBPβ in macrophages can mediate metabolic and immune dysregulations. Therefore, we aimed to explore its role in KCs in MASLD pathogenesis.
Methods:
A 12-week high-fat and high-cholesterol diet (HFHCD) model was used in wild-type or KC-specific Cebpb heterozygous knockout mice (n = 10 per group), followed by liver evaluation using histopathology, flow cytometry, and RNA-seq. RNA-seq of liver tissue (n = 3 per group) and C/EBPβ CUT&Tag-seq of sorted KCs were comprehensively analyzed to elucidate the transcriptional regulatory network. Flow cytometry and immunofluorescence were used to detect the expression or distribution of key proteins.
Results:
HFHCD induced prominent immune cell infiltration and a concomitant increase in C/EBPβ in KCs. KC-specific Cebpb heterozygous knockout significantly reduced HFHCD-induced lobular inflammation (p <0.05) and inflammation-related gene expression (p <0.05) in the liver. Multi-omics analysis revealed increased C/EBPβ activity in KCs in MASLD, leading to a selective promotive effect on MASLD-induced genes. Further integrated analysis identified Vcam1 as a key direct downstream gene of C/EBPβ in KCs in MASLD, which involves C/EBPβ-mediated activation of the Vcam1 promoter. VCAM1 was predominantly expressed in KCs in the hepatic tissue of MASLD mice and patients. KC-expressed VCAM1 was significantly increased in MASLD compared with healthy controls (p <0.01), and it promoted immune cell infiltration into the liver.
Conclusions:
Increased C/EBPβ in KCs promotes pathogenic transcriptional activation, leading to increased VCAM1 expression and inflammatory cell infiltration in MASLD. Inhibition of C/EBPβ in KCs might be a potential therapeutic strategy against hepatic inflammation in MASLD.
Impact And Implications:
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, but its pathogenesis remains elusive. In this study, we investigated the critical role of CCAAT/enhancer binding protein β (C/EBPβ) in Kupffer cells and its implications in MASLD pathogenesis. We found that an increased C/EBPβ level in Kupffer cells promotes hepatic inflammation in MASLD by upregulating VCAM1 expression. Our findings provide valuable insights into the molecular mechanisms driving MASLD and propose a potential novel therapeutic target to mitigate hepatic inflammation in MASLD.
Insights
Increased C/EBPβ in Kupffer cells drives hepatic inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD) by upregulating VCAM1. Targeting C/EBPβ in Kupffer cells offers a potential therapeutic strategy for MASLD.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver condition with incompletely understood inflammatory mechanisms.
- Kupffer cells (KCs) play a role in hepatic inflammation in MASLD, with CCAAT/enhancer binding protein β (C/EBPβ) implicated in macrophage-mediated immune dysregulation.
Purpose of the Study:
- To investigate the role of C/EBPβ in KCs in the pathogenesis of MASLD.
- To elucidate the molecular mechanisms by which C/EBPβ influences hepatic inflammation in MASLD.
Main Methods:
- Utilized a 12-week high-fat and high-cholesterol diet (HFHCD) mouse model with wild-type and KC-specific Cebpb heterozygous knockout mice.
- Employed histopathology, flow cytometry, RNA-seq, and CUT&Tag-seq for comprehensive liver and KC analysis.
- Investigated protein expression and distribution using flow cytometry and immunofluorescence.
Main Results:
- HFHCD induced significant immune cell infiltration and elevated C/EBPβ levels in KCs.
- KC-specific Cebpb knockout reduced lobular inflammation and inflammation-related gene expression in MASLD livers.
- Multi-omics analysis identified increased C/EBPβ activity in KCs, promoting MASLD-associated genes, with Vcam1 identified as a key direct downstream target.
- VCAM1 expression was elevated in KCs in MASLD livers of mice and patients, promoting immune cell infiltration.
Conclusions:
- Elevated C/EBPβ in KCs promotes hepatic inflammation in MASLD via transcriptional activation, leading to increased VCAM1 expression and immune cell infiltration.
- Targeting C/EBPβ in KCs presents a potential therapeutic avenue for mitigating hepatic inflammation in MASLD.
