Early-Life Nutritional and Environmental Factors in the Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease: A DOHaD Perspective.
Abstract
The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that nutritional and environmental exposures during critical developmental periods, including fetal life, the suckling-weaning period, and early adulthood, strongly influence later disease risks. Research on DOHaD has expanded rapidly in recent years. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major risk factor for type 2 diabetes mellitus, hypertension, and atherosclerotic cardiovascular diseases, and its prevalence is increasing in adults, children, and adolescents. Exposures during "the first 1000 d" of life, spanning fetal development to weaning, determine later risk of lifestyle-related diseases. This review summarizes recent epidemiological findings and mechanistic insights from animal DOHaD studies, particularly regarding MASLD. Specifically, drawing on the Barker hypothesis, the modern DOHaD framework, and the mismatch hypothesis, it discusses how maternal obesity, diet quality, early antibiotic exposure, and the timing of breastfeeding and complementary feeding may influence MASLD risk. In animal models, developmental exposure to undernutrition, hypoxia, early weaning, and high-fat/high-sugar diets promotes hepatic lipid accumulation, endoplasmic reticulum stress, inflammation, and fibrosis. The proposed mechanisms include i) leptin resistance and impaired insulin signaling; ii) intestinal barrier breakdown with gut-liver axis inflammation; iii) reduced very-low-density lipoprotein secretion, increased de novo lipogenesis, and impaired β-oxidation; iv) dysregulation of lipid droplet regulators, including cell death inducing DFFA-like effector, perilipins, and phosphatidylcholine/ phosphatidylethanolamine N-methyltransferase; and v) epigenetic memory via DNA methylation and histone modifications. By integrating evidence that prenatal and early-life environments shape susceptibility to MASLD, this review provides deeper insight into MASLD pathogenesis.