ABSTRACT
The molecular details relevant to dietary supplementation of the omega-3 fatty acid DHA in mothers as well as in their offspring are not clear. The PUFA elongase, elongation of very long-chain fatty acid (ELOVL)2, is a critical enzyme in the formation of DHA in mammals. In order to address the question regarding the origin of DHA during perinatal life, we have used DHA-deficient Elovl2-ablated mice as a model system to analyze the maternal impact on the DHA level in their offspring of various genotypes. Elovl2-/- mothers maintained on control diet had significantly lower systemic levels of DHA compared with the Elovl2+/- and Elovl2+/+ mothers. Dietary DHA administration during the pregnancy and lactation periods led to increased DHA accretion in maternal tissues and serum of all genotypes. The proportion of DHA in the liver and serum of the Elovl2-/- offspring was significantly lower than in the Elovl2+/+ offspring. Remarkably, the DHA level in the Elovl2+/- offspring nursed by DHA-free-fed Elovl2-/- mothers was almost as high as in +/+ pups delivered by +/+ mothers, suggesting that endogenous synthesis in the offspring can compensate for maternal DHA deficiency. Maternal DHA supplementation had a strong impact on offspring hepatic gene expression, especially of the fatty acid transporter, Mfsd2a, suggesting a dynamic interplay between DHA synthesis and DHA uptake in the control of systemic levels in the offspring.
Subject(s)
Acetyltransferases/genetics , Docosahexaenoic Acids/metabolism , Liver/metabolism , Membrane Transport Proteins/metabolism , Acetyltransferases/metabolism , Animals , Docosahexaenoic Acids/administration & dosage , Fatty Acid Elongases , Female , Gene Expression Regulation , Genotype , Humans , Liver/pathology , Membrane Transport Proteins/genetics , Mice , Mice, Knockout , Pregnancy , SymportersABSTRACT
Endocrine therapy is the first-line targeted adjuvant therapy for hormone-sensitive breast cancer. In view of the potential anticancer property of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) together with chemotherapy in estrogen receptor alpha (ERα) positive mammary tumors, we have explored the regulation by estradiol of the fatty acid desaturation and elongation enzymes involved in DHA synthesis in the human breast cancer cell line MCF7, which expresses ERα but not ERß. We demonstrate a robust up-regulation in the expression of the fatty acid elongases Elovl2 and Elovl5 upon estradiol stimulation in MCF7 cells, which was sustained for more than 24 hours. Exposure with the ER inhibitor tamoxifen abolished specifically the Elovl2 but not the Elovl5 expression. Similarly, knock-down of ERα eliminated almost fully the Elovl2 but not the Elovl5 expression. Furthermore, ERα binds to one specific ERE within the Elovl2 enhancer in a ligand dependent manner. The involvement of ERα in the control of especially Elovl2, which plays a crucial role in DHA synthesis, may have potential implications in the treatment of breast cancer.
