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Dominant negative effect on male fertility and sperm maturation by haploinsufficiency of ELOVL2 in mouse
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
Howard Hughes Medical Institute, University of Utah, USA.
Laboratoire de Pharmacologie et Toxicologie, INRA, Toulouse.
Biological Chemistry, Centre for Crop Genetic Improvement, Rothamsted Research, UK.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

ELOVL2 is a member of the mammalian microsomal enzyme family (ELOVL) involved in the elongation of very long-chain fatty acids (VLCFAs) including polyunsaturated fatty acids (PUFAs). Specifically, ELOVL2 is suggested to mediate the rate-limiting condensation reaction in the elongation of PUFAs of C20 and C22 carbons in length. These PUFAs are required for various physiological functions including, regulation of the composition and fluidity of cell membranes, signalling and gene expression. Moreover, certain PUFAs can be oxygenated forming eicosanoids which are implicated in a variety of signalling pathways. The expression of Elovl2 is highest in testis and liver, but significant amounts of transcripts can also be found in kidney, brain, lung and white adipose tissue. Here, we show that ablation of Elovl2 in mice results in a complete absence of VLCPUFAs with 24-30 carbon atoms of the n-6 family in the testis, and that these fatty acids are indispensable for normal spermatogenesis and fertility. Ablation of Elovl2 was associated with a complete arrest of spermatogenesis with seminiferous tubule displaying only spermatogonia and primary spermatocytes without further germinal cells. The Elovl2+/- mice exhibited abnormal sperm morphology with rounded, condensed head, instead of the normal elongated and hooked head seen in wild-type mice. Intercrosses of Elovl2+/- mice displayed both pre- and post-meiotic deficiency of spermatogenesis. These results indicate a novel mechanism involving ELOVL2-derived fatty acids in mammalian spermatogenesis.

National Category
Natural Sciences
URN: urn:nbn:se:su:diva-34406OAI: diva2:284668
Available from: 2010-01-12 Created: 2010-01-08 Last updated: 2011-03-18Bibliographically approved
In thesis
1. Metabolic Significance of Fatty Acid Elongation
Open this publication in new window or tab >>Metabolic Significance of Fatty Acid Elongation
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Very long-chain fatty acids (VLCFAs), including polyunsaturated fatty acids (PUFAs), are essential lipids whose functional diversity is made possible by variation in their chain length and degree of unsaturation. Fatty acids can either be derived directly from the diet or they can be synthesized de novo through lipogenesis, up to 16 carbons in length by fatty acid synthase. Further elongation into VLCFAs is catalysed by the enzymes referred to as elongation of very long-chain fatty acids (ELOVLs). Seven ELOVL proteins have been identified, all of which display distinct fatty acid substrate specificity. The enclosed papers discuss issues regarding the regulation, function and contribution to lipid composition of the Elovl genes with special emphasis on Elovl2 and Elovl3.

In primary brown adipocytes the Elovl3 gene was shown to be regulated by all three PPAR isoforms, involving both transcriptional activation and mRNA stability. In an attempt to clarify the role of ELOVL3 in whole-body lipid homeostasis, the metabolic effects associated with Elovl3 ablation in mice were investigated. Elovl3-ablated mice were lean and showed markedly reduced triglyceride and leptin levels in serum. In addition, the mice were completely resistant to diet-induced obesity, associated with a reduced hepatic lipogenic gene expression and triglyceride content.

Over-expression of Elovl2 in cells promoted accumulation of lipid droplets, associated with enhanced fatty acid uptake and induction of PPARγ target genes. To further assess the in vivo function of ELOVL2, the Elovl2 gene was disrupted in mice by homologous recombination. Elovl2-ablated mice exhibited a severe reduction of the elongation products of C24:5n-6 in the testis, indicating a novel role of ELOVL2 in the formation of very-long-chain PUFAs ≥C26. In addition, Elovl2+/- male mice displayed both pre- and post-meiotic deficiency of spermatogenesis. These results specify an indispensable function of ELOVL2-derived fatty acids, which can give new insights into nutritional intervention as an aid in assisting male fertility problems.

Place, publisher, year, edition, pages
Stockholm: Department of Physiology, Stockholm University, 2010. 54 p.
National Category
Research subject
urn:nbn:se:su:diva-34815 (URN)978-91-7155-993-7 (ISBN)
Public defence
2010-02-11, Hörsalen, Frescati backe 107, Svante Arrhenius väg 21 A, Stockholm, 10:00 (English)
At the time of the doctoral defence, the following papers were unpublished and had status as follows: Paper 2: Submitted. Paper 3: Manuscript. Paper 5: Manuscript. Paper 6: Manuscript.Available from: 2010-01-21 Created: 2010-01-12 Last updated: 2011-03-17Bibliographically approved

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Zadravec, DamirJacobsson, Anders
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