Maternal Hypercholesterolemia and Phytosterol Intervention on Oxysterol Concentrations in Newly‐Weaned ApoE Deficient Mice

Abstract

During hypercholesterolemic pregnancies, the fetus is exposed to excessive cholesterol that is thought to increase cardiovascular disease risk in adults. We recently reported that newly‐weaned offspring from hypercholesterolemic apoE−/− mice have increased blood lipid concentrations that are normalized by maternal phytosterol (PS) supplementation throughout gestation and lactation. However, the influence of maternal hypercholesterolemia and PS supplementation on offspring oxysterols, bioactive oxygenated cholesterol derivatives that regulate arterial health and lesion progression, have yet to be addressed. Therefore, we tested the hypothesis that offspring born to hypercholesterolemic mothers would have increased circulating oxysterol concentrations and that pups from PS‐supplemented mothers would have a more favorable serum and hepatic oxysterol profile compared with pups from unsupplemented mothers. Twenty‐one female apoE−/− mice were randomly assigned to three different chow based diets throughout gestation and lactation: chow (chow; control), chow diet with high cholesterol (CH; 0.15% (w/w), and chow diet with 0.15% (w/w) cholesterol and 2% (w/w) phytosterol (CH/PS). On postnatal day 21, offspring were euthanized for serum and hepatic oxysterol profiling and transcriptional changes in hepatic sterol regulatory targets by HPLC and RT‐PCR, respectively. Pups born to hypercholesterolemic mothers had increased (p<0.05) serum cholesterol, 25‐hydroxycholesterol (HC), 7αHC, 7βHC, and 7‐ketocholesterol that were normalized by maternal PS‐supplementation. Hepatic mRNA expression of 7α‐hydroxylase (CYP7A1) was increased (p<0.05) in pups born to hypercholesterolemic mothers but normalized in pups from PS‐supplemented mothers. Compared with the CH group, pups from PS‐supplemented mothers demonstrated increased transcription of liver X receptor (LXR) and its target gene adenosine triphosphate binding cassette G8 (ABCG8). No difference (p>0.05) in the transcription of hepatic oxysterol binding proteins (OSBP 3, 8, and 7) was observed between the groups. These results suggest that, beyond increased circulating cholesterol, newly‐weaned offspring from hypercholesterolemic mothers have enhanced serum oxysterol concentrations and that maternal PS supplementation attenuates this response.Support or Funding InformationSupported by the National Institute for Complementary and Alternative Medicine.