Maternal hypercholesterolemia enhances oxysterol concentration in mothers and newly weaned offspring but is attenuated by maternal phytosterol supplementation

Abstract

In hypercholesterolemic pregnancies, the maternal environment is characterized by excessive levels of atherogenic lipids that may increase cardiovascular disease risk in mothers and their offspring. We examined the influence of maternal hypercholesterolemia and phytosterol (PS) intervention on the concentration and metabolism of oxysterols, bioactive oxygenated cholesterol derivatives that regulate arterial health and lesion progression, in mothers and their newly weaned offspring. Twenty-one female apoE mice were randomly assigned to three different diets throughout gestation and lactation: (1) chow, (2) high cholesterol (CH; 0.15%) and (3) CH with added PS (2%, CH/PS). At the end of the lactation period, mothers and pups were euthanized for serum and hepatic oxysterol analyses, hepatic transcriptional profiling of hepatic sterol regulatory targets and atherosclerosis. Hypercholesterolemic dams and their pups demonstrated increased (P˂.05) serum oxysterols [including 24 hydroxycholesterol (HC), 25HC, 27HC, 7αHC, 7βHC and 7 ketocholesterol)] compared with the chow group that were normalized by maternal PS supplementation. Hepatic oxysterol concentrations followed a similar pattern of response in mothers but were not altered in newly weaned pups. Hepatic mRNA expression suggested a pattern of enhanced abca1/g1 high-density-lipoprotein-mediated efflux but a reduction in biliary abcg5/g8 export in both dams and their pups. Although arterial lesions were not apparent in newly weaned pups, CH dams demonstrated enhanced atherosclerosis that was reduced upon PS intervention. These results demonstrate that offspring from hypercholesterolemic pregnancies have enhanced circulating oxysterol concentrations and highlight the potential utility of PS as a lipid-lowering option during hypercholesterolemic pregnancies for which there are currently limited options.

Excessive early-life cholesterol exposure may have later-life consequences for nonalcoholic fatty liver disease

“…Further, in apoE −/− mice, in addition to increased hepatic cholesterol and TG, newly weaned offspring from MHC dams demonstrated increased hepatic 7-β hydroxycholesterol (7β-HC), an oxysterol marker of oxidative stress. 74,75 These maladaptations in hepatic lipid status were accompanied by alterations in the mRNA and protein expression of cholesterol and fatty acid regulatory targets. In addition to increased hepatic lipid content, 72 newly weaned offspring from hypercholesterolemic apoE −/− mice showed a reduction in hepatic de novo lipogenic gene expression.…”

Malprogramming of Hepatic Lipid Metabolism due to Excessive Early Cholesterol Exposure in Adult Progeny

“…Therefore, using the apoE-deficient mouse model, the objectives of this study were to access hepatic lipid metabolism in adult offspring exposed to excessive early cholesterol as a result of maternal hypercholesterolemia and examine the influence of postnatal diet on these effects. Given the metabolic dysfunction we previously observed in newly-weaned offspring from hypercholesterolemic mothers [39, 40], we anticipated that adult offspring born from hypercholesterolemic mothers would possess altered hepatic lipid metabolism and that these responses would be exacerbated upon consumption of a postnatal western-style diet versus a standard chow diet.…”

Omics analysis of oxysterols to better understand their pathophysiological role

“…ApoE -/mothers fed a high cholesterol diet and their pups exhibited increased serum 7α-HC, 7β-HC, 7-KC, 24S-HC, and 25-hydroxycholesterol (25-HC), but not 27-HC, compared with the ApoE -/chow group; phytosterol intervention reduced oxysterol concentrations in both dams and their offspring upon. Overall, the results demonstrate that a hypercholesterolemic maternal environment during pregnancy and lactation is able to affect oxysterol status in offspring, and point to phytosterols as a suitable CVD risk-reduction strategy either in hypercholesterolemic mothers and in their newly weaned offspring [24].…”