Glucocorticoids and intrauterine programming of nonalcoholic fatty liver disease

Accumulating epidemiological and experimental evidence indicates that nonalcoholic fatty liver disease (NAFLD) has an intrauterine origin. Fetuses exposed to adverse prenatal environments (e.g., maternal malnutrition and xenobiotic exposure) are more susceptible to developing NAFLD after birth. Glucocorticoids are crucial triggers of the developmental programming of fetal-origin diseases. Adverse intrauterine environments often lead to fetal overexposure to maternally derived glucocorticoids, which can program fetal hepatic lipid metabolism through epigenetic modifications. Adverse intrauterine environments program the offspring's glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis, which contributes to postnatal catch-up growth and disturbs glucose and lipid metabolism. These glucocorticoid-driven programming alterations increase susceptibility to NAFLD in the offspring. Notably, after delivery, offspring often face an environment distinct from their in utero life. The mismatch between the intrauterine and postnatal environments can serve as a postnatal hit that further disturbs the programmed endocrine axes, accelerating the onset of NAFLD. In this review, we summarize the current epidemiological and experimental evidence demonstrating that NAFLD has an intrauterine origin and discuss the underlying intrauterine programming mechanisms, focusing on the role of overexposure to maternally derived glucocorticoids. We also briefly discuss potential early life interventions that may be beneficial against fetal-originated NAFLD.