Early Exposure to Phytosterols Reduces Triglycerides and Modulates Hepatic Expression of Lipid-Regulatory Genes in Newly-Weaned ApoE Deficient Mice
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In utero exposure to excessive cholesterol has been shown to increase fetal plasma cholesterol concentration and predispose adult offspring to cardiovascular disease (CVD) risk. As lipid-lowering drugs are contraindicated during pregnancy, natural cholesterol-lowering compounds may be a safe and effective alternative to reduce CVD risk in offspring born to hypercholesterolemic mothers. Using an apolipoprotein E deficient (apoE -/- ) model, we have previously shown that mothers fed a cholesterol-inducing diet supplemented with phytosterols (CH/PS) during pregnancy and lactation reduces blood LDL-cholesterol and triglycerides (TG) in newly-weaned pups compared with pups from unsupplemented mothers (CH). Therefore, the objective of this study was to further characterize the TG-lowering response and associated mechanisms by examining several endpoints including serum VLDL lipoprotein particle characteristics, hepatic TG concentration and fatty acid (FA) composition, and hepatic mRNA expression patterns of lipid-regulatory genes. In addition to a reduction in serum TG, pups from the CH/PS group demonstrated a lower ( p <0.05) total number of VLDL particles (-31%), stemming from reductions in all VLDL subclasses including large (-39%), medium (-40%), and small (-24%) compared with pups from the CH group. However, VLDL size did not differ between the CH and CH/PS groups. No difference in hepatic TG concentrations between the CH and CH/PS groups or in the relative composition of fatty acids was observed between the two groups of pups. Compared with the CH pups, pups born to CH/PS mothers demonstrated a coordinated down-regulation in hepatic genes regulating de novo lipogenesis including PGC1β, SERBP1c, FAS, and ACC. Our results suggest that maternal PS supplementation during pregnancy and lactation favorably modulates TG metabolism in newly-weaned pups by reducing hepatic de novo lipogenic response. Future work will examine if this early benefit is translated into a reduction in cardiovascular disease risk in adulthood.