Effects of prenatal and suckling exposure to Western diet on the lipid metabolism in ApoE-/- mice

In utero environment during embryonic and fetal development is associated with risk of diseases later in life. This concept of fetal programming is further supported by clinical and experimental studies. Previous studies demonstrate that maternal high fat diet intake during early development increase susceptibility to cardiovascular diseases and liver diseases in offspring. However, little is known about the molecular mechanisms underlying the impacts of maternal diet on offspring. We aim to setup a mouse model to characterize the effects of maternal hypercholesterolemia on the lipid metabolism of adult offspring. Apolipoprotein E knockout (ApoE-/-) female mice were fed either a Western diet (WD) or a low-fat control diet (CD) before and during gestation and lactation. At weaning, the ApoE-/- offspring were all fed WD, generating two experimental groups: W-W and C-W offspring. Female mice gave birth to three litters. Among them, the offspring of litter 1 and 2 were analyzed at 23 weeks of age, and the offspring of litter 3 were investigated at 16 weeks of age. Biochemical analysis showed that the W-W offspring from litter 1 and 2 have a higher serum triglycerides (TG) and cholesterol levels than C-W offspring at weaning. However, there are no significant differences on hepatic TG and cholesterol levels, adipocyte area as well as the severity of atherosclerotic lesions between W-W and C-W offspring at 23 weeks of age. In contrast to the results from litter 1, and 2, more profound differences between two groups were observed in litter 3. The relative weight of liver, inguinal white adipose tissue (iWAT) and interscapular brown adipose tissue (iBAT) was significantly higher in W-W than in C-W offspring. Although there were no significant differences on the development of atherosclerotic lesions, W-W offspring from litter 3 showed hepatic steatosis combined with accumulation of hepatic TG and cholesterol in comparison with C-W group. This accumulation was associated with up-regulation of de novo lipid synthesis. Increased expressions of lipid synthesis related genes, including Fasn, Acacb, Lipe, Chpt1, Srebf1 and Srebf2 were observed in the livers of W-W offspring. In addition, the expression of cholesterol transport related genes, such as Abcg5 and Abcg8 was significantly higher in the livers of W-W in those of C-W offspring. Taken together, our findings demonstrate that maternal hypercholesterolemia increase susceptibility to lipid accumulation in their adult offspring by augmenting hepatic lipid synthesis, which is mediated at least in part by increased expression of lipid synthesis and transport related genes. Future research will concentrate on epigenetic changes involved in this programming process.