Fetal Origin of Nonalcoholic Fatty Liver Disease

With the emergence of the “Developmental Origins of Health and Disease” theory, it has been established that adverse intrauterine conditions can increase the susceptibility of offspring to nonalcoholic fatty liver disease (NAFLD) in cases of intrauterine growth retardation. However, a comprehensive theoretical framework underlying the occurrence of fetal-originated NAFLD is still lacking. Recent studies have revealed that various adverse prenatal environments lead to fetal overexposure to maternal glucocorticoids, which results in epigenetic programming changes in genes related to the glucocorticoid-insulin-like growth factor 1 axis, hypothalamic-pituitary-adrenal axis, and hepatic lipid metabolic function. Following birth, offspring exhibit catch-up growth and ectopic fat deposition based on the intrauterine programming changes under adequate nutritional conditions, thereby accelerating the onset of NAFLD. This chapter summarizes the research progress on fetal-originated NAFLD and its intrauterine programming mechanism and proposes the “two-programming and two-strike” mechanism of NAFLD. These mechanisms provide a theoretical and experimental basis for early clinical warning, diagnosis, and treatment of NAFLD.