Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3. Issue 5 (30th January 2020)

• Record Type: Journal Article
• Authors: Fang, Jing; Ji, Yan‐Xiao; Zhang, Peng; Cheng, Lin; Chen, Yue; Chen, Jun; Su, Yanfang; Cheng, Xu; Zhang, Yan; Li, Tianyu; Zhu, Xuehai; Zhang, Xiao‐Jing; Wei, Xiang
• Is Part Of: Hepatology. Volume 71:Issue 5(2020)
• Page Start: 1592
• Page End: 1608
• Publication Date: 2020-01-30
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.30950
• Languages: English
• ISSNs: 0270-9139

Abstract

Abstract : Background and Aims: Although knowledge regarding the pathogenesis of nonalcoholic fatty liver disease (NAFLD) has profoundly grown in recent decades, the internal restrictive mechanisms remain largely unknown. We have recently reported that the transcription repressor interferon regulatory factor‐2 binding protein 2 (IRF2BP2) is enriched in cardiomyocytes and inhibits pathological cardiac hypertrophy in mice. Notably, IRF2BP2 is abundantly expressed in hepatocytes and dramatically down‐regulated in steatotic livers, whereas the role of IRF2BP2 in NAFLD is unknown. Approach and Results: Herein, using gain‐of‐function and loss‐of‐function approaches in mice, we demonstrated that while hepatocyte‐specific Irf2bp2 knockout exacerbated high‐fat diet–induced hepatic steatosis, insulin resistance and inflammation, hepatic Irf2bp2 overexpression protected mice from these metabolic disorders. Moreover, the inhibitory role of IRF2BP2 on hepatosteatosis is conserved in a human hepatic cell line in vitro . Combinational analysis of digital gene expression and chromatin immunoprecipitation sequencing identified activating transcription factor 3 (ATF3) to be negatively regulated by IRF2BP2 in NAFLD. Chromatin immunoprecipitation and luciferase assay substantiated the fact that IRF2BP2 is a bona fide transcription repressor of ATF3 gene expression via binding to its promoter region. Functional studies revealed that ATF3 knockdown significantly relieved IRF2BP2 knockout‐exaggerated hepatosteatosis in vitro . Conclusion: IRF2BP2 is an integrative restrainer in controlling hepatic steatosis, insulin resistance, and inflammation in NAFLD through transcriptionally repressing ATF3 gene expression.