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Dnmt1/Tet2-mediated changes in Cmip methylation regulate the development of nonalcoholic fatty liver disease by controlling the Gbp2-Pparγ-CD36 axis

 Jangho Lee  ;  Ji-Hye Song  ;  Jae-Ho Park  ;  Min-Yu Chung  ;  Seung-Hyun Lee  ;  Sae-Bom Jeon  ;  So Hee Park  ;  Jin-Taek Hwang  ;  Hyo-Kyoung Choi  
 EXPERIMENTAL AND MOLECULAR MEDICINE, Vol.55(1) : 143-157, 2023-01 
Journal Title
Issue Date
Adaptor Proteins, Signal Transducing / metabolism ; Animals ; CD36 Antigens / genetics ; CD36 Antigens / metabolism ; DNA Methylation ; DNA-Binding Proteins / metabolism ; Dioxygenases* / genetics ; Dioxygenases* / metabolism ; GTP-Binding Proteins / metabolism ; Humans ; Liver / metabolism ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease* / genetics ; Non-alcoholic Fatty Liver Disease* / metabolism ; PPAR gamma / genetics ; PPAR gamma / metabolism
Dynamic alteration of DNA methylation leads to various human diseases, including nonalcoholic fatty liver disease (NAFLD). Although C-Maf-inducing protein (Cmip) has been reported to be associated with NAFLD, its exact underlying mechanism remains unclear. Here, we aimed to elucidate this mechanism in NAFLD in vitro and in vivo. We first identified alterations in the methylation status of the Cmip intron 1 region in mouse liver tissues with high-fat high-sucrose diet-induced NAFLD. Knockdown of DNA methyltransferase (Dnmt) 1 significantly increased Cmip expression. Chromatin immunoprecipitation assays of AML12 cells treated with oleic and palmitic acid (OPA) revealed that Dnmt1 was dissociated and that methylation of H3K27me3 was significantly decreased in the Cmip intron 1 region. Conversely, the knockdown of Tet methylcytosine dioxygenase 2 (Tet2) decreased Cmip expression. Following OPA treatment, the CCCTC-binding factor (Ctcf) was recruited, and H3K4me3 was significantly hypermethylated. Intravenous Cmip siRNA injection ameliorated NAFLD pathogenic features in ob/ob mice. Additionally, Pparγ and Cd36 expression levels were dramatically decreased in the livers of ob/ob mice administered siCmip, and RNA sequencing revealed that Gbp2 was involved. Gbp2 knockdown also induced a decrease in Pparγ and Cd36 expression, resulting in the abrogation of fatty acid uptake into cells. Our data demonstrate that Cmip and Gbp2 expression levels are enhanced in human liver tissues bearing NAFLD features. We also show that Dnmt1-Trt2/Ctcf-mediated reversible modulation of Cmip methylation regulates the Gbp2-Pparγ-Cd36 signaling pathway, indicating the potential of Cmip as a novel therapeutic target for NAFLD.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Lee, Seung Hyun(이승현) ORCID logo https://orcid.org/0000-0001-7549-9430
Jeon, Sae-Bom(전새봄) ORCID logo https://orcid.org/0000-0002-0206-5532
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