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ELOVL2 and PUFA biosynthesis: Impact on sex-specific processes in mammals
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. (Anders Jacobsson)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Endogenously synthesized PUFAs (Polyunsaturated Fatty Acids) vary in production depending on medical conditions, gender, developmental phase, age, fertility status, pregnancy and lactation. PUFA biosynthesis is further regulated via amount of dietary intake as well as genetically. A key player in the PUFA biosynthesis enzyme machinery is the fatty acid elongase Elongation of very long-chain fatty acids 2 (ELOVL2) that is essential for the production of the omega-3 PUFA docosahexaenoic acid (DHA, 22:6 n-3) that has many beneficial health effects. In the omega-6 PUFA series, ELOVL2 produces docosapentaenoic acid (DPA n-6, 22:5 n-6). Specifically, ELOVL2 enables the elongation of PUFA with 22 carbons to generate precursors of 24 carbons for the generation of the previously mentioned end products as well as very long-chain (VLC) PUFA up to C34.

This thesis elucidates that estrogen has the power to modulate ELOVL2 expression in breast cancer cells and that this probably is due to ligand dependent binding of the estrogen receptor alpha (ERα) to the Elovl2 enhancer. In addition, estrogen via ERα modulates hepatic levels of Elovl2 in mice in a gender specific manner. Ablation of Elovl2 leads to whole body deficiency of DHA. The thesis unravels that systemic DHA levels in neonatal mice is determined both by the ELOVL2 status of the mother and the offspring. Ablation of Elovl2 also leads to impaired spermatogenesis and infertility in male mice. However, heterozygous Elovl2-ablated mice, differ in fertility potency depending on strain. Here we show that this discrepancy is linked to an altered ratio between saturated and mono-unsaturated fatty acids and VLC-PUFA moieties of glucosylceramides in testis.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2016. , 64 p.
National Category
Biophysics
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-134356ISBN: 978-91-7649-549-0 (print)ISBN: 978-91-7649-550-6 (print)OAI: oai:DiVA.org:su-134356DiVA: diva2:1033054
Public defence
2016-11-15, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius väg 20, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Accepted. Paper 2: Manuscript. Paper 3: Manuscript. Paper 4: Manuscript.

Available from: 2016-10-21 Created: 2016-10-05 Last updated: 2017-08-14Bibliographically approved
List of papers
1. Estrogen Enhances the Expression of the Polyunsaturated Fatty Acid Elongase Elovl2 via ERa in Breast Cancer Cells
Open this publication in new window or tab >>Estrogen Enhances the Expression of the Polyunsaturated Fatty Acid Elongase Elovl2 via ERa in Breast Cancer Cells
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, e0164241Article in journal (Refereed) Published
Abstract [en]

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 (ER alpha) 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 ER alpha but not ER beta. 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, knockdown of ER alpha eliminated almost fully the Elovl2 but not the Elovl5 expression. Furthermore, ER alpha binds to one specific ERE within the Elovl2 enhancer in a ligand dependent manner. The involvement of ER alpha in the control of especially Elovl2, which plays a crucial role in DHA synthesis, may have potential implications in the treatment of breast cancer.

National Category
Biological Sciences
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-137515 (URN)10.1371/journal.pone.0164241 (DOI)000389604900014 ()
Available from: 2017-01-18 Created: 2017-01-09 Last updated: 2017-08-14Bibliographically approved
2. Sex differences in the control of PUFA-synthesizing enzymes by estrogen in mice
Open this publication in new window or tab >>Sex differences in the control of PUFA-synthesizing enzymes by estrogen in mice
(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-134359 (URN)
Available from: 2016-10-05 Created: 2016-10-05 Last updated: 2016-10-18Bibliographically approved
3. Both maternal and offspring Elovl2 genotypes determine systemic DHA levels in perinatal mice
Open this publication in new window or tab >>Both maternal and offspring Elovl2 genotypes determine systemic DHA levels in perinatal mice
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2017 (English)In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 58, no 1, 111-123 p.Article in journal (Refereed) Published
Abstract [en]

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.(Jlr) 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.

Keyword
docosahexaenoic acid synthesis, polyunsaturated fatty acid, elongation of very long-chain fatty acid 2, supplementation, pregnancy, lactation, docosahexaenoic acid
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-140398 (URN)10.1194/jlr.M070862 (DOI)000392408700009 ()27864326 (PubMedID)
Available from: 2017-03-16 Created: 2017-03-16 Last updated: 2017-08-14Bibliographically approved
4. Elovl2 haploinsufficient C57Bl/6 but not 129/Sv mice are infertile due to impaired levels of glucosylceramide fatty acid moities in testis
Open this publication in new window or tab >>Elovl2 haploinsufficient C57Bl/6 but not 129/Sv mice are infertile due to impaired levels of glucosylceramide fatty acid moities in testis
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(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-134360 (URN)
Available from: 2016-10-05 Created: 2016-10-05 Last updated: 2016-10-18Bibliographically approved

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