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A Novel Foodstuff Restored Aberrant Dna Methylation Patterns In Western Diet Induced-MASLD Mice

ABSTRACT: Background: Aberrant DNA methylation patterns play an important role in the development of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) development. Diets rich in fiber and antioxidants could potentially reverse these patterns. We have previously demonstrated that supplementation with AncestryR, a mixture of Mexican foods (nopal, cocoa, and crickets), exerts a curative effect on MASLD; however, the impact of Ancestry on DNA methylation remains unclear.

ORGANISM(S): Mus musculus

PROVIDER: GSE289914 | GEO | 2025/12/01

REPOSITORIES: GEO

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Project description:Hispanics of Mexican American descent in South Texas show a very high prevalence of MASLD, with some studies reporting rates as high as 50% in adults. However, assessment of genetic risk factors underlying this prevalence is complicated by a high co-occurrence of other metabolic disorders and variable endogenous and exogenous environmental risk factors. To map the genetic architecture of MASLD hepatic steatosis risk, we conducted an epidemiological-scale investigation using human induced pluripotent stem cell (iPSC)-derived hepatocyte cultures from 193 participants in our longitudinal South Texas Family Study (STFS). iPSC-based models offer greater power to map genetic risk factors by experimentally controlling for confounding organismal and environmental factors. We combined transcriptome-wide gene expression analysis with high-content cellular measurements of neutral lipids to define a core hepatic steatosis MASLD phenotype at baseline (vehicle-treated) and following a lipid challenge. The additive genetic heritability of hepatic steatosis measures was 0.44 (p-value = 0.03) at baseline and 0.42 (p-value = 0.03) at post-lipid-challenge. Multivariable linear regression comparing each gene’s expression against hepatic steatosis measures identified 1,070 genes at baseline and 1,229 genes post-lipid challenge, whose expression showed a transcriptome-wide statistically significant association (standardized |β| ≥ 0.24; Bonferroni-corrected p-value ≤ 0.001) with baseline and post-lipid challenge hepatic steatosis measures, respectively. Functional annotation and pathway enrichment analyses of these genes implicated a broad range of hepatocellular functions, mapping an overall genetic architecture of MASLD-associated steatosis risk in Mexican Americans. The genes whose expression was positively correlated with hepatic steatosis measures suggest a direct role of variation in fatty acid (FA) and cholesterol uptake, de novo lipogenesis (DNL), and carbohydrate shunts in hepatic steatosis risk, as well as a cellular stress-associated and high-turnover metabolic state marked by elevated FA-oxidation and ketogenesis. In contrast, the genes whose expression was inversely correlated with hepatic steatosis measures suggest a significant role of the cellular cytoskeleton, hepatocyte epithelial integrity, and endosomal and autophagic clearance machinery in steatosis risk.

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A Novel Foodstuff Restored Aberrant Dna Methylation Patterns In Western Diet Induced-MASLD Mice

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