biostudies-literatureMagdy ANational Research Council of Science and TechnologyKorea National Institute of HealthKorea Health Industry Development InstituteMinistry of Health and WelfareNational Research Foundation of KoreaSeoul Metropolitan Government Seoul National University Boramae Medical CenterAging Convergence Research CenterKorea Research Institute of Bioscience and Biotechnology824-844https://www.ebi.ac.uk/biostudies/studies/S-EPMC11540403biostudies-literatureUnknown30(4)<h4>Background/aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.Clinical and molecular hepatologyDNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease.PMC115404032023R1A2C10033392022M3A9B60176542022ER090202RS-2023-00223831KGM519242304-2023-003304-2023-00322021M3A9E4021818CRC22013-400RS-2024-00440883HI21C05382021R1A2C2005820Kim HJPark JLMagdy AKang KWSohn HAChoi MKim MJung HJGo HHaam KKwon ESKim WLee DHYoo TLee JMfalseDNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease.<h4>Background/aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.2024-01-01T00:00:00Z2024 Oct2026-06-01T20:38:35.36Z2025-04-04T11:41:50.198ZS-EPMC115404033904852210.3350/cmh.2024.0229