ELOVL2 controls the level of n-6 28:5 and 30:5 fatty acids in testis, a prerequisite for male fertility and sperm maturation in mice

Damir Zadravec; Petr Tvrdik; Hervé Guillou; Richard Haslam; Tsutomu Kobayashi; Johnathan A. Napier; Mario R. Capecchi; Anders Jacobsson

doi:10.1194/jlr.M011346

ELOVL2 controls the level of n-6 28:5 and 30:5 fatty acids in testis, a prerequisite for male fertility and sperm maturation in mice

^*The Wenner-Gren Institute, Arrhenius Laboratories F3, Stockholm University, Stockholm, Sweden
^†Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT
^§Laboratoire de Pharmacologie et Toxicologie, Institut National de la Recherche Agronomique, Toulouse, France
^**Department of Biological Chemistry, Rothamsted Research, Harpenden, United Kingdom

Abstract

ELOVL2 is a member of the mammalian microsomal ELOVL fatty acid enzyme family, involved in the elongation of very long-chain fatty acids including PUFAs required for various cellular functions in mammals. Here, we used ELOVL2-ablated (Elovl2^−/−) mice to show that the PUFAs with 24–30 carbon atoms of the ω-6 family in testis are indispensable for normal sperm formation and fertility in male mice. The lack of Elovl2 was associated with a complete arrest of spermatogenesis, with seminiferous tubules displaying only spermatogonia and primary spermatocytes without further germinal cells. Furthermore, based on acyl-CoA profiling, heterozygous Elovl2^+/− male mice exhibited haploinsufficiency, with reduced levels of C28:5 and C30:5n-6 PUFAs, which gave rise to impaired formation and function of haploid spermatides. These new insights reveal a novel mechanism involving ELOVL2-derived PUFAs in mammals and previously unrecognized roles for C28 and C30 n-6 PUFAs in male fertility. In accordance with the function suggested for ELOVL2, the Elovl2^−/− mice show distorted levels of serum C20 and C22 PUFAs from both the n-3 and the n-6 series. However, dietary supplementation with C22:6n-3 could not restore male fertility to Elovl2^+/− mice, suggesting that the changes in n-6 fatty acid composition seen in the testis of the Elovl2^+/− mice, cannot be compensated by increased C22:6n-3 content.

Footnotes

↵1 To whom correspondence should be addressed. e-mail: anders.jacobsson{at}wgi.su.se
Abbreviations:

DHA

docosahexaenoic acid

dNTP

deoxynucleoside triphosphate

ELOVL

elongation of very-long-chain fatty acid (protein)

ES

embryonic stem (cells)

FAME

fatty acid methyl ester

Hz

heterozygous

KO

knockout

TK

thymidine kinase

VLCFA

very-long-chain FA
This work was supported by grants from the Swedish Research Council and Cancer Foundation (A.J.), Sven och Dagmar Saléns stiftelse (D.Z.), Institut National de la Recherche Agronomique, and Formas (H.G. and A.J.). Rothamsted Research receives grant support from the Biotechnology and Biological Sciences Research Council, United Kingdom (J.N.).