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Fetal Physiological Programming

Maternal dietary iron restriction modulates hepatic lipid metabolism in the fetuses

¹Endocrinology and Metabolism Unit, Developmental Origins of Health and Disease (DOHaD) Division, School of Medicine, University of Southampton, Southampton General Hospital, and ²Centre for DOHaD, University of Southampton, Princess Anne Hospital, Southampton; and ³Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom

Submitted 26 May 2004 ; accepted in final form 7 September 2004

Maternal dietary Fe restriction reduced fasting plasma cholesterol and triglyceride (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 27% (P < 0.05) increase in cholesterol but 29% reduction (P = 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 50% (P < 0.01) and 34% (P < 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 43% (P < 0.001) reduction in mRNA levels of SREBP-1c and its response genes, including acetyl-CoA carboxylase by 35% (P = 0.01), fatty acid synthase by 18% (P = 0.05), and diacylglycerol acyltransferase by 19% (P = 0.03). Furthermore, protein levels of CD36 were reduced by 27% (P = 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

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