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

Abstract

ObjectiveAn 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.ResultsSerum 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.

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

“…In support of these findings, we have recently shown that MHC during the gestation period is associated with hepatic TG accumulation in fetal apoE −/− mice 80 which is similarly linked to a reduction in hepatic lipogenic mRNA expression. This response was similar to what we observed in newly weaned and adult males exposed to MHC throughout gestation and lactation described earlier 74,76 ( Table 2), suggesting that the programming of hepatic dysfunction in adulthood may originate in utero.…”

“…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. 74 Similarly, newly weaned pups from hypercholesterolemic hamsters demonstrated increased hepatic cholesterol accompanied with elevated LDLr and HMGCoAr protein content despite no change in SREBP2 protein levels. 73 The adaptations in newly weaned offspring described above can be linked to direct exposure to excessive cholesterol, whether in utero or through the suckling of maternal milk with modified nutrient (e.g., cholesterol, TG) or hormonal composition.…”

“…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

“…Gene expression was analyzed using the 2(-delta delta C t) method. Sequences of sense and antisense primers for target and housekeeping genes were based on previously published reports for β-actin, fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), carnitine palmitoyltransferase 1a (CPT1a), 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAr), sterol regulatory element-binding protein (SREBP) 1c, SREBP2, microsomal triglyceride transfer protein (MTP), diglyceride acyltransferase (DGAT), and apolipoprotein B (apoB) [44].…”

Bitkisel Sterollerin/Stanollerin Aterosklerotik Süreç ve Kardiyovasküler Hastalıklar Üzerine Etkisi

“…33 Son çalışmalardan elde edilen bulgular; bitkisel sterollerin bağırsak kolesterolü emilimini (azalmış kolesterol emilimi, artmış fekal kolesterol kaybı) azaltarak ve hepatik kolesterol sentezinde görevli genlerin ifadesini (artan HMG-CoA redüktaz mRNA) değiştirerek kolesterol seviyelerini düşürdüğünü vurgulamaktadır. 14,[34][35][36] Ayrıca, bitkisel sterollerin, 27-hidroksikolesterol üretimi, karaciğer X reseptörü alfa aktivasyonunun inhibisyonu ve insan kolon adenokarsinoma hücre dizisi (Caco-2) enterositlerinde bazolateral sterol taşıyıcısı olan ATP bağlayıcı kaset A1 (ABCA1) ifadesi ile kolesterol emilimini azaltabileceği görüşü de mevcuttur. 37 Randomize kontrollü çalışmaların yer aldığı bir meta analiz çalışmasında, bitkisel sterollerin/stanollerin TK, LDL-K ve trigliserit (TG) konsantrasyonları üzerinde benzer düşürücü etkileri olduğu bildirilmiştir.…”