Gestational hypercholesterolemia programs hepatic steatosis in a sex-specific manner in ApoE-deficient mice

Abstract

Maternal hypercholesterolemia (MHC), a pathological condition characterized by an exaggerated rise in maternal serum cholesterol during pregnancy, may influence offspring hepatic lipid metabolism and increase the risk of nonalcoholic fatty liver disease (NAFLD). As NAFLD is characterized by a sexual dimorphic response, we assessed whether early-life exposure to excessive cholesterol influences the development of NAFLD in offspring and whether this occurs in a sex-specific manner. Female apoE−/− mice were randomly assigned to a control (CON) or a high cholesterol (CH; 0.15%) diet prior to breeding. At parturition, a cross-fostering approach was used to establish three groups: (1) normal cholesterol exposure throughout gestation and lactation (CON-CON); (2) excessive cholesterol exposure throughout gestation and lactation (CH-CH); and (3) excessive cholesterol exposure in the gestation period only (CH-CON). Adult male offspring (PND 84) exposed to excessive cholesterol during gestation only (CH-CON) demonstrated hepatic triglyceride (TG) accumulation and reduced lipogenic gene expression. However, male mice with a prolonged cholesterol exposure throughout gestation and lactation (CH-CH) had a similar, but not exacerbated hepatic response. Further, with the exception of higher serum TG in adult CH-CH females, evidence for a programming effect in female offspring was largely absent in comparison with males. These results indicate a sexual dimorphic response with respect to the effect of MHC on later life hepatic steatosis and highlight the gestation period as the most influential malprogramming window for hepatic lipid dysfunction in males.