SRA

Nutrient-derived folates carry one-carbon units to biosynthesis pathways, driving cellular growth and repair pathways. However, in adults, physiological effects of dietary folate deficiency (FD) or excess supply remain understudied. We report that FD shifts systemic fuel preference to glucose over fatty acids. In the liver, FD inhibits PPARs and induces progression to fatty liver. The fatty liver of FD mice is selectively enriched in health-promoting polyunsaturated fatty acids over monounsaturated species and presents bile detoxification, suggesting active protective programs. Moreover, FD redirects cysteine usage in transsulfuration towards glutathione and H2S, a profile providing clinical relevance in redox-regulation and novel insights for signaling of dietary status through gasotransmitters. Furthermore, we show that excess folate (or folinic acid) poses paradoxical FD-state in the brain with direct implications on supplement safety. Altogether, our evidence highlights the tissue-specific and dose-dependent roles of dietary folate as key regulator of fuel-usage and anabolic metabolism in adults.