Gestational Hypercholesterolemia Programs NAFLD in a Sex-Specific Manner in ApoE-Deficient Mice (P11-140-19)

Abstract

Abstract Objectives Two separate studies were conducted to determine if gestational hypercholesterolemia alters fetal hepatic lipid metabolism (study 1) and programs nonalcoholic fatty liver disease (NAFLD) in a sex-specific manner in adult offspring (study 2). Methods Study 1: 12 female apoE−/− mice were randomly assigned to two different chow-based diets throughout gestation: chow (CON; control) or chow diet with cholesterol (CH; 0.15%). On gestation day 18, fetuses were euthanized and samples amalgamated for evaluation of serum, hepatic, and placental lipid profiling and transcriptional changes in hepatic microRNA (miRNA). Study 2: 18 female apoE−/− mice were randomly assigned to the same diets as above but throughout both the gestation and lactation periods. At birth, litters were cross-fostered with surrogate CON and CH dams to generate three experimental groups (n = 6/group; gestation exposure-lactation exposure): (CON-CON; control), (CH-CH; positive control), and (CH-CON). On postnatal day 21, one male and one female from each litter were weaned on to a chow diet until adulthood (postnatal day 84) and euthanized for serum and hepatic lipid profiling. Results Study 1: Fetuses from CH dams possessed increased (P < 0.05) hepatic triglycerides (TG) which was accompanied with a down regulation (P < 0.05) of the hepatic lipogenic genes fatty acid synthase (-1.8 fold, FAS), acetyl-CoA carboxylase (-1.6 fold, ACC), and sterol regulatory element-binding protein 1c (-1.2 fold, SREBP1c). Furthermore, fetal livers from CH mothers showed increased miRNA-27a (+ 1.9 fold) and reduced miRNA-200c expression (-1.8 fold) (P < 0.05). Study 2: Compared to CON-CON, CH-CH and CH-CON male offspring demonstrated increased (P < 0.05) serum TG and hepatic cholesterol and TG concentrations. With the exception of increased (P < 0.05) serum TG in CH-CH adult female offspring, which was normalized in CH-CON females, no differences (P > 0.05) in serum and hepatic lipids were observed in female offspring between treatment groups. Conclusions In apoE−/- mice, exposure to excessive cholesterol during gestation alters fetal hepatic lipid and miRNA status and programs NALFD in a sex-specific manner in adult male offspring only. Funding Sources Supported by the National Institute for Complementary and Alternative Medicine.