Maternal palmitic acid overload establishes a SETD1A-dependent epigenetic memory that programs offspring susceptibility to metabolic liver disease

Maternal palmitic acid overload establishes a SETD1A-dependent epigenetic memory that programs offspring susceptibility to metabolic liver disease | Research Square Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Maternal palmitic acid overload establishes a SETD1A-dependent epigenetic memory that programs offspring susceptibility to metabolic liver disease Salvador Benitah, Claudia Bigas, Josefina Martín, Masaki Kimura, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8949727/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Metabolic dysfunction-associated fatty liver disease (MASLD) has emerged as a major global health concern, with prevalence rising alarmingly in the pediatric population. Maternal nutrition and maternal body mass index (BMI) influence the propensity of the offspring to develop MASLD during childhood and adulthood, but the mechanisms underlying this maternal inheritance are unknown. Here, we have explored the developmental origins of MASLD, focusing on the effect of maternal nutrition and its epigenetic consequences in offspring. Using a mouse model, we demonstrate that maternal consumption of a Palmitic Acid-enriched High-Fat and high-sugar Diet (PA-HFD) during pregnancy and lactation induces stable epigenetic modifications, particularly related to H3K4me3 deposition, in the liver of male offspring through the action of the histone methyltransferase SET1a/COMPASS. This imprinting establishes a persistent transcriptional reprogramming, notably an enrichment in genes governing fatty acid β-oxidation, generating a fasted hepatocyte-like phenotype. Integrated transcriptomic, proteomic and metabolomic analyses reveal that upon re-exposure to a HFD in adulthood, this epigenetically primed hepatic state drives exaggerated metabolic responses, including lipidome reprogramming, leading to exacerbated hepatic steatosis, peroxisomal hyperactivation, oxidative stress, toxic lipid accumulation, and impaired glucose tolerance. Importantly, these gene expression and lipidome changes predict the severity of metabolic liver disease later in life, and can be recapitulated in human pluripotent stem cell-derived hepatocytes when Plamitic Acid is exposed in developmental stage. Moreover, genetic or pharmacological inhibition of SETD1A/COMPASS eliminates the priming marks, restores hepatic transcriptomic programs, and reduces circulating insulin levels and hepatic steatosis in vivo. Together, our findings identify a mechanistic epigenetic link between maternal nutrition and lifelong MASLD susceptibility and uncover a therapeutic strategy to erase the intergenerational transmission of MASLD predisposition. Biological sciences/Physiology Biological sciences/Physiology/Metabolism/Fat metabolism Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information

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