Maternal dietary iron restriction modulates hepatic lipid metabolism in the fetuses

Abstract

(TG) concentrations in the fetuses, as well as decreased plasma TG levels in the adult offspring. To investigate how maternal Fe restriction was affecting fetal lipid metabolism, we investigated whether there were changes in liver lipid metabolism in the full-term fetuses. There was a ϳ27% (P Ͻ 0.05) increase in cholesterol but ϳ29% reduction (P ϭ 0.01) in TG concentrations in the liver of the Fe-restricted fetuses. Hepatic mRNA levels of cholesterol 7␣ hydroxylase and liver X receptor-␣ (LXR␣) were reduced by ϳ50% (P Ͻ 0.01) and ϳ34% (P Ͻ 0.01), respectively. As LXR␣ regulates expression of sterol response element binding protein-1c (SREBP-1c) expression, we measured SREBP-1c expression. There was an ϳ43% (P Ͻ 0.001) reduction in mRNA levels of SREBP-1c and its response genes, including acetyl-CoA carboxylase by ϳ35% (P ϭ 0.01), fatty acid synthase by ϳ18% (P ϭ 0.05), and diacylglycerol acyltransferase by ϳ19% (P ϭ 0.03). Furthermore, protein levels of CD36 were reduced by ϳ27% (P ϭ 0.02) in Fe-restricted fetuses. In conclusion, changes in liver cholesterol and TG concentrations in Fe-restricted fetuses may be coordinated through reduced expression of heme-containing cholesterol 7␣ hydroxylase and its regulator LXR␣, mainly via downregulation of expression of genes in bile acid synthesis and fatty acid synthesis pathways. cholesterol; cholesterol 7 alpha hydroxylase; liver X receptor-alpha; fetus ABNORMALITIES IN LIPID METABOLISM are associated with the metabolic syndrome, Type 2 diabetes and coronary heart disease (45). Plasma lipid profile may be affected by a change in development before birth, which has been referred to as the "fetal origins," "thrifty phenotype," or "fetal programming" hypothesis (3,16,17,30). This hypothesis is supported by data from epidemiological and animal studies. For example, people who had a small abdominal circumference at birth had raised serum concentrations of total cholesterol and low-density lipoprotein-cholesterol and apolipoprotein B in adulthood (2). People exposed to famine in early gestation had a more atherogenic lipid profile than did those who were not exposed to famine in utero (38). In animal studies, maternal dietary protein restriction during either (both) gestation or (and) lactation reduces total cholesterol and high-density lipoproteincholesterol in the rat offspring (31). Increased dietary cholesterol intake in the mother during gestation increases long-term progression of atherosclerosis in the rabbit offspring (33), and treatment of the mother with vitamin E or cholestyramine during gestation markedly reduces the progression of atherogenic lesions in the aorta of these offspring (33). In the rat, maternal calorie restriction causes hyperphagia, obesity, and hypertension in the rat offspring (48), and maternal dietary Fe restriction reduces offspring plasma triglyceride (TG) concentrations (29). Thus these data suggest that a change in maternal physiology may have a long-lasting effect on lipid metabolism in the offspring.Fe deficiency is a common nutritio...

Maternal Protein Restriction Elevates Cholesterol in Adult Rat Offspring Due to Repressive Changes in Histone Modifications at the Cholesterol 7α-Hydroxylase Promoter

“…However, very little is known about how maternal nutrition may alter cholesterol homeostasis in postnatal life. In one study, maternal dietary iron restriction led to a 21% decrease in fetal growth and an increase in fetal liver cholesterol (21). This was further associated with decreased expression of Cyp7a1 (21).…”

“…In one study, maternal dietary iron restriction led to a 21% decrease in fetal growth and an increase in fetal liver cholesterol (21). This was further associated with decreased expression of Cyp7a1 (21). More recently, a LP diet throughout pregnancy in mice was demonstrated to lead to reduced LXR␣ expression at embryonic d 19.5 (22); however the long-term effects of this in utero nutritional insult on cholesterol homeostasis in postnatal life remain elusive.…”

Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans

“…The association seems to also hold true in reverse. Several studies found that reduction of iron by several different methods led to amelioration of adiposity and improvement of obesity and obesity-related diseases (Zhang et al 2005;Fleming and Ponka 2012;Tajima et al 2012; Moreno-Navarrete et al 2014a,b). Unfortunately, the mechanisms of this association between iron and lipid accumulation or obesity remain largely unclear.…”

Maternal Undernutrition and Long-Term Effects on Hepatic Function

“…These offspring also exhibited decreased hepatic and circulating insulin growth factor 1 (Igf-1) which is critical for insulin function, glucose metabolism, and growth [52]. While other models of maternal dietary-induced IUGR led to hypercholesterolemia in postnatal life, uterine ligation appears to have no effect on cholesterol homeostasis unless the offspring were challenged with a high-fat diet in postnatal life [34,53,54]. Although this animal model is physiologically relevant to idiopathic IUGR, it is distinct from dietary-induced undernutrition as it leads to direct decreases in both oxygen and nutrients to the fetus.…”