Clin Mol Hepatol.
2024 Oct;30(4):824-844. 10.3350/cmh.2024.0229.
DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease
- Magdy A1,2
- Kim HJ1
- Go H1,2
- Lee JM1,2
- Sohn HA1
- Haam K1
- Jung HJ1
- Park JL1,2
- Yoo T3
- Kwon ES1,4
- Lee DH5
- Choi M3
- Kang KW6
- Kim W
5 - Kim M1,2
- on behalf of the Innovative Target Exploration of NAFLD (ITEN) Consortium1
- Affiliations
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- 1Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- 2Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
- 3Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- 4Department of Biomolecular Science, KRIBB School of Bioscience, UST, Daejeon, Korea
- 5Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
- 6College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
- KMID: 2560088
- DOI: http://doi.org/10.3350/cmh.2024.0229
Abstract
- Background/Aims
Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction–associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD.
Methods
Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction–associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing.
Results
Methylome and transcriptome analyses of liver biopsies revealed significant (p<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA<, and SERPING1, as well as hypomethylation (p<0.0005) and upregulation (p<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data.
Conclusions
Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.
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