한빛사논문
- 조회316
Kim, Doyoon1,2; Shah, Masaud1; Kim, Jang Hyun1,2; Kim, JungMo3; Baek, Yang-Hyun4; Jeong, Jin-Sook5; Han, Sang-Young6; Lee, Yong Sun7; Park, Gaeul8; Cho, Jin-Han9; Roh, Young-Hoon10; Lee, Sung-Wook11; Choi, Gi-Bok12; Park, Jong Hoon13; Yoo, Kyung Hyun13; Seong, Rho Hyun14; Lee, Yeon-Su8; Woo, Hyun Goo1,2,3
1Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
2Department of Biomedical Science, Graduate School, Ajou University, Suwon, Republic of Korea
3Ajou Translational Omics Center (ATOC), Research Institute for Innovative Medicine, Ajou University Medical Center, Suwon, Republic of Korea
4Liver Center, Department of Internal Medicine, Dong-A University College of Medicine, Busan, Republic of Korea
5Pathology & Laboratory Medicine, St Mary’s Hospital, Busan, Republic of Korea
6Liver Center, On Hospital, Busan, Republic of Korea
7Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea
8Division of Rare Cancer, Research Institute, National Cancer Center, Goyang, Republic of Korea
9Department of Diagnostic Radiology, Dong-A University Medical Center, Busan, Republic of Korea
10Department of Surgery, Dong-A University Medical Center, Busan, Republic of Korea
11Liver Center, Department of Internal Medicine, Dong-A University Medical Center, Busan, Republic of Korea
12Department of Radiology, On Hospital, Busan, Republic of Korea
13Department of Biological Sciences, Sookmyung Women’s University, Seoul, Republic of Korea
14Department of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea
Doyoon Kim, Masaud Shah These authors contributed equally to this work.
Correspondence Hyun Goo Woo, Yeon-Su Lee
Abstract
Background aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a broad and continuous spectrum of liver diseases ranging from fatty liver to steatohepatitis. The intricate interactions of genetic, epigenetic, and environmental factors in the development and progression of MASLD remain elusive. Here, we aimed to achieve an integrative understanding of the genomic and transcriptomic alterations throughout the progression of MASLD.
Approach results: RNA-Seq profiling (n=146) and whole-exome sequencing (n=132) of MASLD liver tissue samples identified three transcriptomic subtypes (G1-G3) of MASLD, which were characterized by stepwise pathological and molecular progression of the disease. Macrophage-driven inflammatory activities were identified as a key features for differentiating these subtypes. This subtype-discriminating macrophage interplay was significantly associated with both the expression and genetic variation of the dsDNA sensor IFI16 (rs6940, A>T, T779S), establishing it as a fundamental molecular factor in MASLD progression. The in vitro dsDNA-IFI16 binding experiments and structural modeling revealed that the IFI16 variant exhibited increased stability and stronger dsDNA binding affinity compared to the wild-type. Further downstream investigation suggested that the IFI16 variant exacerbated DNA sensing-mediated inflammatory signals via mitochondrial dysfunction-related signaling of the IFI16-PYCARD-CASP1 pathway.
Conclusions: This study unveils a comprehensive understanding of MASLD progression through transcriptomic classification, highlighting the crucial roles of IFI16 variants. Targeting the IFI16-PYCARD-CASP1 pathway may pave the way for the development of novel diagnostics and therapeutics for MASLD.
논문정보
- Research article
- 2024년 02월 (BRIC 등록일 2024-02-23)
- 국내 연구진
- 의약학 > 유전 및 유전체의학
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