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Both maternal and offspring Elovl2 genotypes determine systemic DHA levels in perinatal mice
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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Number of Authors: 7
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.

Place, publisher, year, edition, pages
2017. Vol. 58, no 1, 111-123 p.
Keyword [en]
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: urn:nbn:se:su:diva-140398DOI: 10.1194/jlr.M070862ISI: 000392408700009PubMedID: 27864326OAI: oai:DiVA.org:su-140398DiVA: diva2:1082281
Available from: 2017-03-16 Created: 2017-03-16 Last updated: 2017-11-29Bibliographically approved
In thesis
1. ELOVL2 and PUFA biosynthesis: Impact on sex-specific processes in mammals
Open this publication in new window or tab >>ELOVL2 and PUFA biosynthesis: Impact on sex-specific processes in mammals
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:nbn:se:su:diva-134356 (URN)978-91-7649-549-0 (ISBN)978-91-7649-550-6 (ISBN)
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
2. Metabolic Significance of Systemic DHA Deficiency
Open this publication in new window or tab >>Metabolic Significance of Systemic DHA Deficiency
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fatty acid composition in the body displays a high level of heterogeneity and can rapidly respond to changes in diet regime or to starvation. Homeostasis of the level of certain fatty acids is an important factor for maintenance of structural integrity as well as for proper signaling within the organism. Hence, changes in fatty acid composition have been proposed as an important factor during the pathogenesis of many diseases.Concentration of polyunsaturated fatty acid (PUFA) within the body is modulated by the interplay between dietary intake, endogenous de novo synthesis or mobilization of fatty acids from tissue reservoirs. Endogenous synthesis of PUFA is regulated on different genetic levels as well as the level of substrate availability. Studies have reported a variation in PUFA biosynthesis between different developmental stages, age, gender, during pregnancy, lactation and under conditions of certain disorders. A member of the enzymatic machinery involved in PUFA synthesis is the elongase Elongation of very long-chain fatty acids 2 (ELOVL2) that controls the elongation of PUFA with 22 carbons to produce 24 carbons precursors for the production of the omega-3 PUFA, docosahexaenoic acid (DHA, 22:6n3) and the omega-6 PUFA, docosapentaenoic (DPAn6, 22:5n6). Deletion of Elovl2 in a mouse model (Elovl2KO) leads to systemic DHA deficiency at different physiological and early lifestages, and is related to certain metabolic dysfunctions. Mitochondria of Elovl2KO mice display structural and functional impairment. Compared to wild type littermates, Elovl2KO mice do not gain as much weight after high-fat diet treatment and do not develop hepatic steatosis, despite having a higher level of the positive regulator of denovo lipogenesis, nuclear transcription factor SREBP1c. Resistance to high fat diet induced-obesity in Elovl2KO mice is abolished by DHA supplementation together with high sucrose content in the background diet. In conclusion, deletion of Elovl2 in mice leads to systemic DHA deficiency that has pleiotropic effect on mouse energy metabolism.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2016. 71 p.
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-134089 (URN)978-91-7649-555-1 (ISBN)978-91-7649-556-8 (ISBN)
Public defence
2016-11-11, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 14, 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 2: Manuscript. Paper 3: Manuscript. Paper 4: Manuscript.

Available from: 2016-10-19 Created: 2016-09-30 Last updated: 2017-08-14Bibliographically approved

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Pauter, Anna M.Gonzalez-Bengtsson, AmandaTalamonti, EmanuelaAsadi, AbolfazlDethlefsen, OlgaJacobsson, Anders
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