Maternal protein restriction during gestation in rodents is widely used as a model of developmental programming; however, its metabolic effects in offspring are often modest. In humans, protein deficiency is frequently accompanied by deficiencies in essential micronutrients. This study examined whether maternal choline insufficiency, an essential micronutrient whose deficiency in adult rodents induces metabolic dysfunction-associated steatotic liver disease, modifies the metabolically restrained hepatic phenotype conferred by maternal protein restriction in offspring. Pregnant ICR mice were fed a control, a protein-restricted diet (8% of total energy from protein), or a protein- and choline-restricted diet (25% of the standard choline content, w/w) from gestational day 1. Male offspring were weaned onto a high-fat, high-sucrose diet, as a standardized metabolic challenge, and hepatic histology, biochemical parameters, and metabolic- and oxidative stress-related gene and protein expression were analyzed. Maternal protein restriction alone did not induce hepatic steatosis in offspring and was associated with reduced expression of lipid metabolism-related genes (Apoa4) and decreased hepatic activity of xanthine oxidoreductase (XOR), a key enzyme involved in reactive oxygen species production. In contrast, maternal choline insufficiency combined with protein restriction induced hepatic steatosis compared with maternal protein restriction alone, accompanied by lipid droplet hypertrophy, increased expression of inflammatory genes (Il1b and Il18), and reactivation of hepatic XOR activity, together with restoration of metabolic gene expression toward control levels, in the offspring. Together, these findings demonstrate that maternal choline insufficiency abolishes the metabolically restrained hepatic phenotype induced by gestational protein restriction and promotes progression to hepatic steatosis in offspring.
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