Diet intervention altered DNA methylation of potassium voltage-gated channel subfamily Q member 1 in metabolic dysfunction-associated steatohepatitis

BACKGROUND: Lifestyle interventions are cornerstones of metabolic dysfunction-associated fatty liver disease (MASLD) management, and differential DNA methylation of potassium voltage-gated channel subfamily Q member 1 (KCNQ1) was involved in MASLD-related diseases. However, little is known about the DNA methylation mechanism of KCNQ1 underlying the effect of lifestyle interventions on the most common liver disease. OBJECTIVE: This study aimed to investigate the role of DNA methylation of KCNQ1 in metabolic dysfunction-associated steatohepatitis (MASH) after diet intervention. METHODS: This study utilized 38 male C57BL/6 mice (9-week-old, SPF grade). Following a 1-week acclimatization period, animals were randomly allocated to receive either a methionine-choline deficient (MCD, n = 23) or methionine-choline sufficient (MCS, n = 15) dietary regimen for 4 weeks. Seven mice per group were subsequently euthanized for MASH model validation. After confirming successful model establishment, remaining MASH mice underwent randomized allocation to four-week interventions: low-fat diet (LFD, n = 8), continued MCD feeding (n = 8), or control MCS maintenance (n = 8). Genomic DNA methylation patterns in hepatic and adipose tissues were analyzed using methylation-sensitive restriction enzyme sequencing (MethylRAD). For LFD-treated MASH specimens, EpiTYPER mass spectrometry and quantitative reverse transcription PCR were employed to assess DNA methylation status and transcriptional expression of KCNQ1, respectively. RESULTS: Hypermethylation in the intron of KCNQ1 was observed after LFD intervention in the liver and adipose tissue of MASH mice (p < 0.05) with MethylRAD sequencing. High DNA methylation and low mRNA expression of KCNQ1 were validated in adipose tissue of MASH mice in response to LFD (p < 0.05) with the EpiTYPER array. CONCLUSIONS: The study reinforced the role of DNA methylation in regulating gene expression of KCNQ1 in response to LFD intervention and highlighted that the DNA methylation of KCNQ1 in MASH adipose tissue could be tissue-specific. All these results contribute to elucidating the molecular mechanisms underlying the activities of DNA methylation in MASH.