Differential Regulation of Hepatic Transcription Factors in the Wistar Rat Offspring Born to Dams Fed Folic Acid, Vitamin B12 Deficient Diets and Supplemented with Omega-3 Fatty Acids

Abstract

Nutritional status of the mother is known to influence various metabolic adaptations required for optimal fetal development. These may be mediated by transcription factors like peroxisome proliferator activated receptors (PPARs), which are activated by long chain polyunsaturated fatty acids. The objective of the current study was to examine the expression of different hepatic transcription factors and the levels of global methylation in the liver of the offspring born to dams fed micronutrient deficient (folic acid and vitamin B12) diets and supplemented with omega-3 fatty acids. Female rats were divided into five groups (n = 8/group) as follows; control, folic acid deficient (FD), vitamin B12 deficient (BD) and omega-3 fatty acid supplemented groups (FDO and BDO). Diets were given starting from pre-conception and continued throughout pregnancy and lactation. Pups were dissected at the end of lactation. Liver tissues were removed; snap frozen and stored at −80°C. Maternal micronutrients deficiency resulted in lower (p<0.05) levels of pup liver docosahexaenoic acid (DHA) and arachidonic acid (ARA) as compared to the control group. Pup liver PPARα and PPARγ expression was lower (p<0.05) in the BD group although there were no differences in the expression of SREBP-1c, LXRα and RXRα expression. Omega-3 fatty acids supplementation to this group normalized (p<0.05) levels of both PPARα and PPARγ but reduced (p<0.05) SREBP-1c, LXRα and RXRα expression. There was no change in any of the transcription factors in the pup liver in the FD group. Omega-3 fatty acids supplementation to this group reduced (p<0.05) PPARα, SREBP-1c and RXRα expression. Pup liver global methylation levels were higher (p<0.01) in both the micronutrients deficient groups and could be normalized (p<0.05) by omega-3 fatty acid supplementation. Our novel findings suggest a role for omega-3 fatty acids in the one carbon cycle in influencing the hepatic expression of transcription factors in the offspring.

Organ-Specific Gene Expression Changes in the Fetal Liver and Placenta in Response to Maternal Folate Depletion

“…However, previous studies have used transcriptomic approaches to investigate gene expression changes in the liver in response to low folate-containing diets [33,34,35,36,44,45] so we compared our data with outcomes from these studies. Whilst there were differences in gene expression profiles between studies, likely to be due to differences in rodent models, diet composition, duration and timing of the nutrient insult and the particular transcriptomic approaches employed (Table 10), we uncovered a key set of genes which were differentially expressed in the liver in response to low dietary folate/methyl donor intake across multiple studies (Table 11).…”

Effect of prenatal DHA supplementation on the infant epigenome: results from a randomized controlled trial

“…In other studies, an effect of DHA on methylation in the placenta via the alteration of one carbon metabolism has been proposed [19, 20]. In adult humans, differences in DNA methylation have been identified between people with high and low n-3 PUFA intakes [21, 22], and n-3 PUFA supplementation has been shown to induce changes in methylation at specific CpG sites [23].…”

Beneficial effects of omega‐3 fatty acids and vitamin B12 supplementation on brain docosahexaenoic acid, brain derived neurotrophic factor, and cognitive performance in the second‐generation Wistar rats

“…Abbreviations: BDNF, brain derived neurotrophic factor; CREB, cAMP response element-binding protein; DHA, docosahexaenoic acid; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; RME, reference memory error; RWME, reference working memory error; Trk, tropomyosin receptor kinase; WME, working memory error. fatty acids like docosahexaenoic acid (DHA) in the one carbon cycle [14][15][16][17][18].…”