Differential DNA methylation of steatosis and non-alcoholic fatty liver disease in adolescence

Abstract

Background and aims Epigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence, we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks. Approach and results We performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially methylated CpG sites (dmCpGs) for which ≥ 2 probes per gene remained significant across four statistical models with a nominal p value < 0.007. EWAS identified dmCpGs related to three genes (ANK1, MIR10a, PTPRN2) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced (ANK1 n = 6, MIR10a n = 7, PTPRN2 n = 3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p < 2.3 × 10–3). Conclusions We identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies. Graphical abstract

Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in metabolic dysfunction associated Steatotic liver disease (MASLD)

“…Since altered DNA methylation has been identified as a key determinant of MASLD pathogenesis ( Li et al, 2018 ; Hyun and Jung, 2020 ; Lai et al, 2020 ; Bu et al, 2022 ; Kuramoto et al, 2022 ; Melton et al, 2023 ), we next applied Infinium mouse methylation Beadchip array studies to map genome-wide DNA methylation changes in liver biopsies of WT and hepatocyte-specific PPARα KO mice, following 6-week chow or CDAHFD diet. As shown in Figure 4 , the WT mice on a CDAHFD show predominant hypermethylation of the promotor region of PPARα compared to the WT mice on a chow diet, which could explain the gradual silencing of PPARα expression following a 6-week CDAHFD diet.…”

Synergistic Differential DNA Demethylation Activity of Danshensu (Salvia miltiorrhiza) Associated with Different Probiotics in Nonalcoholic Fatty Liver Disease

“…Nowadays, it is a global medical issue, and more than 25% of the general population worldwide suffers from NAFLD [59]. Epigenetic modifications combined with NAFLD are related to type 2 diabetes mellitus and other metabolic diseases [60,61]. Physiological changes in adolescence in short intervals contribute to dysmetabolism, which may lead to early liver damage [62].…”

The relationship between folic acid and nonalcoholic fatty liver disease

“…Many studies have confirmed DNA methylation changed in liver biopsy of patients with NAFLD 45,[47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] (Figure 3). A recent investigation revealed a marked reduction in global DNA methylation among 47 individuals diagnosed with NAFLD compared to a cohort of 18 lean subjects without NAFLD, as assessed via liver biopsy.…”