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Metabolic Significance of Systemic DHA Deficiency
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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: urn:nbn:se:su:diva-134089ISBN: 978-91-7649-555-1ISBN: 978-91-7649-556-8OAI: oai:DiVA.org:su-134089DiVA: diva2:998755
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: 2016-10-10Bibliographically approved
List of papers
1. Elovl2 ablation demonstrates that systemic DHA is endogenously produced and is essential for lipid homeostasis in mice
Open this publication in new window or tab >>Elovl2 ablation demonstrates that systemic DHA is endogenously produced and is essential for lipid homeostasis in mice
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2014 (English)In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 55, no 4, 718-728 p.Article in journal (Refereed) Published
Abstract [en]

The potential role of endogenously synthesized polyunsaturated fatty acids (PUFAs) is a highly overlooked area. Elongation of very long chain (ELOVL) fatty acids in mammals is catalyzed by the ELOVL enzymes to which the PUFA elongase ELOVL2 belongs. To determine its in vivo function, we have investigated how ablation of ELOVL2, which is highly expressed in liver, affects hepatic lipid composition and function in mice. The Elovl2 ablated mice displayed substantial decreased levels of 22:6(n3), docosahexaenoic acid (DHA), and 22:5(n6), docosapentaenoic acid (DPAn6), followed by an accumulation of 22:5(n3) and 22:4(n6) in both liver and serum showing that ELOVL2 primarily controls the elongation process of PUFAs with 22 carbons to produce 24 carbon precursors for DHA and DPA(n6) formation in vivo. The impaired PUFA levels positively influenced hepatic levels of the key lipogenic transcriptional regulator sterol regulatory element binding protein 1c (SREBP1c) as well as its downstream target genes. Surprisingly, the Elovl2 ablated mice were resistant against hepatic steatosis and diet induced weight gain implying that hepatic DHA synthesis via ELOVL2, except controlling de novo lipogenesis, also regulates lipid storage and fat mass expansion in an SREBP1c independent fashion. The changes in fatty acid metabolism were reversed by dietary supplementation with DHA.

Keyword
fatty acid elongase, elongase of very longchain fatty acid 2, docosahexaenoic acid, liver steatosis, weight gain
National Category
Biological Sciences
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-104591 (URN)10.1194/jlr.M046151 (DOI)000336425600010 ()
Note

AuthorCount:7;

Available from: 2014-01-31 Created: 2014-06-11 Last updated: 2016-10-06Bibliographically approved
2. Synergistic effect of DHA and sucrose on body weight gain in Elovl2-/- mice
Open this publication in new window or tab >>Synergistic effect of DHA and sucrose on body weight gain in Elovl2-/- mice
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(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-134085 (URN)
Available from: 2016-09-30 Created: 2016-09-30 Last updated: 2016-10-06Bibliographically 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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(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-134086 (URN)
Available from: 2016-09-30 Created: 2016-09-30 Last updated: 2016-10-06Bibliographically approved
4. Elovl2-ablation leads to mitochondrial DHA-deficiency and reduced oxidative phosphorylation efficiency in mouse liver
Open this publication in new window or tab >>Elovl2-ablation leads to mitochondrial DHA-deficiency and reduced oxidative phosphorylation efficiency in mouse liver
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(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-134088 (URN)
Available from: 2016-09-30 Created: 2016-09-30 Last updated: 2016-10-06Bibliographically approved

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Pauter, Anna Maria
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