Maternal high-fat feeding in pregnancy programs atherosclerotic lesion size in the ApoE*3 Leiden mouse.

Periods of rapid growth seen during the early stages of fetal development, including cell proliferation and differentiation, are greatly influenced by the maternal environment. We demonstrate here that over-nutrition, specifically exposure to a high-fat diet in utero, programed the extent of atherosclerosis in the offspring of ApoE*3 Leiden transgenic mice. Pregnant ApoE*3 Leiden mice were fed either a control chow diet (2.8% fat, n=12) or a high-fat, moderate-cholesterol diet (MHF, 19.4% fat, n=12). Dams were fed the chow diet during the suckling period. At 28 days postnatal age wild type and ApoE*3 Leiden offspring from chow or MHF-fed mothers were fed either a control chow diet (n=37) or a diet rich in cocoa butter (15%) and cholesterol (0.25%), for 14 weeks to induce atherosclerosis (n=36). Offspring from MHF-fed mothers had 1.9-fold larger atherosclerotic lesions (P<0.001). There was no direct effect of prenatal diet on plasma triglycerides or cholesterol; however, transgenic ApoE*3 Leiden offspring displayed raised cholesterol when on an atherogenic diet compared with wild-type controls (P=0.031). Lesion size was correlated with plasma lipid parameters after adjustment for genotype, maternal diet and postnatal diet (R 2=0.563, P<0.001). ApoE*3 Leiden mothers fed a MHF diet developed hypercholesterolemia (plasma cholesterol two-fold higher than in chow-fed mothers, P=0.011). The data strongly suggest that maternal hypercholesterolemia programs later susceptibility to atherosclerosis. This is consistent with previous observations in humans and animal models.

Regulation of gene transcription by fatty acids.

Dietary fat is well recognised as an important macronutrient that has major effects on growth, development and health of all animals including humans. The amount and type of fat in the diet impacts on many aspects of metabolism including lipoprotein pathways, lipid synthesis and oxidation, adipocyte differentiation and cholesterol metabolism. It has become increasingly apparent that many of these effects may be due to direct modulation of expression of key genes through the interaction of fatty acids with certain transcription factors. Peroxisome proliferator-activated receptors (PPARs), the liver X receptors (LXRs), hepatic nuclear factor 4 (HNF-4) and sterol regulatory binding proteins (SREBPs) represent four such factors. This review focuses on emerging evidence that the activity of these transcription factors are regulated by fatty acids and the interactions between them may be responsible for many of the effects of fatty acids on metabolism and the development of chronic disease.