Skip to main content Accessibility help

Maternal diets deficient in folic acid and related methyl donors modify mechanisms associated with lipid metabolism in the fetal liver of the rat

  • Christopher J. McNeil (a1), Susan M. Hay (a1), Garry J. Rucklidge (a1), Martin D. Reid (a1), Gary J. Duncan (a1) and William D. Rees (a1)...


Previously we have examined the effects of diets deficient in folic acid ( − F) or folate deficient with low methionine and choline ( − F LM LC) on the relative abundance of soluble proteins in the liver of the pregnant rat. In the present study we report the corresponding changes in the fetal liver at day 21 of gestation. The abundance of eighteen proteins increased when dams were fed the − F diet. When dams were fed the − F LM LC diet, thirty-three proteins increased and eight decreased. Many of the differentially abundant proteins in the fetal liver could be classified into the same functional groups as those previously identified in the maternal liver, namely protein synthesis, metabolism, lipid metabolism and proteins associated with the cytoskeleton and endoplasmic reticulum. The pattern was consistent with reduced cell proliferation in the − F LM LC group but not in the − F group. Metabolic enzymes associated with lipid metabolism changed in both the − F and − F LM LC groups. The mRNA for carnitine palmitoyl transferase were up-regulated and CD36 (fatty acid translocase) down-regulated in the − F group, suggesting increased mitochondrial oxidation of fatty acids as an indirect response to altered maternal lipid metabolism. In the − F LM LC group the mRNA for acetyl CoA carboxylase was down-regulated, suggesting reduced fatty acid synthesis. The mRNA for transcriptional regulators including PPARα and sterol response element-binding protein-1c were unchanged. These results suggest that an adequate supply of folic acid and the related methyl donors may benefit fetal development directly by improving lipid metabolism in fetal as well as maternal tissues.


Corresponding author

*Corresponding author: Dr William D. Rees, fax +44 1224 716622, email


Hide All
1De Wals, P, Tairou, F, Van Allen, MI, et al. (2007) Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med 357, 135142.
2Relton, CL, Pearce, MS & Parker, L (2005) The influence of erythrocyte folate and serum vitamin B12 status on birth weight. Br J Nutr 93, 593599.
3Anna, E & Beaudin, P (2007) Folate-mediated one-carbon metabolism and neural tube defects: balancing genome synthesis and gene expression. Birth Defects Res C Embryo Today 81, 183203.
4Dunlevy, LP, Burren, KA, Mills, K, et al. (2006) Integrity of the methylation cycle is essential for mammalian neural tube closure. Birth Defects Res A Clin Mol Teratol 76, 544552.
5Burdge, GC, Hanson, MA, Slater-Jefferies, JL, et al. (2007) Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life? Br J Nutr 97, 10361046.
6Lillycrop, KA, Phillips, ES, Jackson, AA, et al. (2005) Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135, 13821386.
7Torrens, C, Brawley, L, Anthony, FW, et al. (2006) Folate supplementation during pregnancy improves offspring cardiovascular dysfunction induced by protein restriction. Hypertension 47, 982987.
8Jackson, AA, Dunn, RL, Marchand, MC, et al. (2002) Increased systolic blood pressure in rats induced by a maternal low-protein diet is reversed by dietary supplementation with glycine. Clin Sci (Lond) 103, 633639.
9Maloney, CA, Hay, SM & Rees, WD (2009) The effects of feeding rats diets deficient in folic acid and related methyl donors on the blood pressure and glucose tolerance of the offspring. Br J Nutr 101, 13331340.
10Maloney, CA, Hay, SM & Rees, WD (2007) Folate deficiency during pregnancy impacts on methyl metabolism without affecting global DNA methylation in the rat fetus. Br J Nutr 97, 10901098.
11McNeil, CJ, Hay, SM, Rucklidge, G, et al. (2008) Disruption of lipid metabolism in the liver of the pregnant rat fed folate deficient and methyl donor deficient diets. Br J Nutr 99, 262271.
12Higuchi, N, Kato, M, Shundo, Y, et al. (2008) Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease. Hepatol Res 38, 11221129.
13American Institute of Nutrition (1977) Report of the American Institute of Nutrition ad hoc committee on standards for nutritional studies. J Nutr 107, 340348.
14Maloney, CA, Lilley, C, Cruickshank, M, et al. (2005) The expression of growth-arrest genes in the liver and kidney of the protein-restricted rat fetus. Br J Nutr 94, 1218.
15Chanson, A, Sayd, T, Rock, E, et al. (2005) Proteomic analysis reveals changes in the liver protein pattern of rats exposed to dietary folate deficiency. J Nutr 135, 25242529.
16Meneses-Lorente, G, Watt, A, Salim, K, et al. (2006) Identification of early proteomic markers for hepatic steatosis. Chem Res Toxicol 19, 986998.
17Marten, NW, Hsiang, CH, Yu, L, et al. (1999) Functional activity of hepatocyte nuclear factor-1 is specifically decreased in amino acid-limited hepatoma cells. Biochim Biophys Acta 1447, 160174.
18Vabulas, RM & Hartl, FU (2005) Protein synthesis upon acute nutrient restriction relies on proteasome function. Science 310, 19601963.
19Fleming, JV, Hay, SM, Harries, DN, et al. (1998) Effects of nutrient deprivation and differentiation on the expression of growth-arrest genes (gas and gadd) in F9 embryonal carcinoma cells. Biochem J 330, 573579.
20Schlessinger, J (2000) Cell signaling by receptor tyrosine kinases. Cell 103, 211225.
21Maurer, A, Wieland, T, Meissl, F, et al. (2005) The β-subunit of G proteins is a substrate of protein histidine phosphatase. Biochem Biophys Res Commun 334, 11151120.
22Dovas, A & Couchman, JR (2005) RhoGDI: multiple functions in the regulation of Rho family GTPase activities. Biochem J 390, 19.
23McNeil, CJ, Hay, SM, Rucklidge, G, et al. (2009) Gene and protein expression profiles in the foetal liver of the pregnant rat fed a low protein diet. Gene Nutr (epublication ahead of print version 30 May 2009).
24Bischoff, FR, Krebber, H, Kempf, T, et al. (1995) Human RanGTPase-activating protein RanGAP1 is a homologue of yeast Rna1p involved in mRNA processing and transport. Proc Natl Acad Sci U S A 92, 17491753.
25Fisher, EA & Ginsberg, HN (2002) Complexity in the secretory pathway: the assembly and secretion of apolipoprotein b-containing lipoproteins. J Biol Chem 277, 1737717380.
26Qiu, W, Kohen-Avramoglu, R, Rashid-Kolvear, F, et al. (2004) Overexpression of the endoplasmic reticulum 60 protein ER-60 downregulates ApoB100 secretion by inducing its intracellular degradation via a nonproteasomal pathway: evidence for an ER-60-mediated and pCMB-sensitive intracellular degradative pathway. Biochemistry 43, 48194831.
27Gerke, V & Moss, SE (2002) Annexins: from structure to function. Physiol Rev 82, 331371.
28Preiss, D & Sattar, N (2008) Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci 115, 141150.
29Ravnskjaer, K, Boergesen, M, Rubi, B, et al. (2005) Peroxisome proliferator-activated receptor α (PPARα) potentiates, whereas PPARγ attenuates, glucose-stimulated insulin secretion in pancreatic β-cells. Endocrinology 146, 32663276.
30Sandberg, MB, Bloksgaard, M, Duran-Sandoval, D, et al. (2005) The gene encoding acyl-CoA-binding protein is subject to metabolic regulation by both sterol regulatory element-binding protein and peroxisome proliferator-activated receptor α in hepatocytes. J Biol Chem 280, 52585266.
31Ameen, C, Linden, D, Larsson, BM, et al. (2004) Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver. Am J Physiol Endocrinol Metab 287, E1039E1048.



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed