Transcriptional control of enterohepatic lipid regulatory targets in response to early cholesterol and phytosterol exposure in apoE(−/−) mice

OBJECTIVE: An excessive rise in blood lipids during pregnancy may promote metabolic dysfunction in adult progeny. We characterized how maternal phytosterol (PS) supplementation affected serum lipids and the expression of lipid-regulatory genes in the intestine and liver of newly-weaned apo-E deficient offspring from dams fed a chow diet supplemented with cholesterol (0.15%, CH) or cholesterol and PS (2%) (CH/PS) throughout pregnancy and lactation. RESULTS: Serum lipid concentrations and lipoprotein particle numbers were exacerbated in offspring from cholesterol-supplemented mothers but normalized to chow-fed levels in pups exposed to PS through the maternal diet during gestation and lactation. Compared with the CH pups, pups from PS-supplemented mothers demonstrated higher (p < 0.05) expression of the primary intestinal cholesterol transport protein (Niemann-Pick C1-like 1) and the rate-limiting enzyme in hepatic cholesterol synthesis (HMG-CoAr), suggestive of a compensatory response to restore cholesterol balance. Furthermore, pups from PS-supplemented mothers exhibited a coordinated downregulation (p < 0.05) of several genes regulating fatty acid synthesis including PGC1β, SREBP1c, FAS, and ACC compared with the CH group. These results suggest that maternal PS supplementation during hypercholesterolemic pregnancies protects against aberrant lipid responses in newly-weaned offspring and results in differential regulation of cholesterol and lipid regulatory targets within the enterohepatic loop.