Acyl-CoA synthetase 6 enriches seminiferous tubules with theω-3 fatty acid docosahexaenoic acid and is required for male fertility in the mouse

Benjamin J. Hale, Regina F. Fernandez, Sora Q. Kim, Victoria D. Diaz, Shelley N. Jackson, Lei Liu, James T Brenna, Brian P. Hermann, Christopher B. Geyer, Jessica M. Ellis

Research output: Contribution to journalArticle

Abstract

Docosahexaenoic acid (DHA) is an ω-3 dietary-derived polyunsaturated fatty acid of marine origin enriched in testes and necessary for normal fertility, yet the mechanisms regulating the enrichment of DHA in the testes remain unclear. Long-chain ACSL6 (acyl-CoA synthetase isoform 6) activates fatty acids for cellular anabolic and catabolic metabolism by ligating a CoA to a fatty acid, is highly expressed in testes, and has high preference for DHA. Here, we investigated the role of ACSL6 for DHA enrichment in the testes and its requirement for male fertility. Acsl6-/- males were severely subfertile with smaller testes, reduced cauda epididymal sperm counts, germ cell loss, and disorganization of the seminiferous epithelium. Total fatty acid profiling of Acsl6-/- testes revealed reduced DHA and increasedω-6 arachidonic acid, a fatty acid profile also reflected in phospholipid composition. Strikingly, lipid imaging demonstrated spatial redistribution of phospholipids in Acsl6-/- testes. Arachidonic acid-containing phospholipids were predominantly interstitial in control testes but diffusely localized across Acsl6-/- testes. In control testes, DHA-containing phospholipids were predominantly within seminiferous tubules, which contain Sertoli cells and spermatogenic cells but relocalized to the interstitium in Acsl6-/- testes. Taken together, these data demonstrate that ACSL6 is an initial driving force for germ cell DHA enrichment and is required for normal spermatogenesis and male fertility.

Original languageEnglish (US)
Pages (from-to)14394-14405
Number of pages12
JournalJournal of Biological Chemistry
Volume294
Issue number39
DOIs
StatePublished - Jan 1 2019

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Coenzyme A Ligases
Seminiferous Tubules
Docosahexaenoic Acids
Fertility
Testis
Fatty Acids
Phospholipids
Arachidonic Acid
Cells
Germ Cells
Coenzyme A
Unsaturated Fatty Acids
Metabolism
Seminiferous Epithelium
Protein Isoforms
Acyl Coenzyme A
Sperm Count
Sertoli Cells
Spermatogenesis
Lipids

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Acyl-CoA synthetase 6 enriches seminiferous tubules with theω-3 fatty acid docosahexaenoic acid and is required for male fertility in the mouse. / Hale, Benjamin J.; Fernandez, Regina F.; Kim, Sora Q.; Diaz, Victoria D.; Jackson, Shelley N.; Liu, Lei; Brenna, James T; Hermann, Brian P.; Geyer, Christopher B.; Ellis, Jessica M.

In: Journal of Biological Chemistry, Vol. 294, No. 39, 01.01.2019, p. 14394-14405.

Research output: Contribution to journalArticle

Hale, Benjamin J. ; Fernandez, Regina F. ; Kim, Sora Q. ; Diaz, Victoria D. ; Jackson, Shelley N. ; Liu, Lei ; Brenna, James T ; Hermann, Brian P. ; Geyer, Christopher B. ; Ellis, Jessica M. / Acyl-CoA synthetase 6 enriches seminiferous tubules with theω-3 fatty acid docosahexaenoic acid and is required for male fertility in the mouse. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 39. pp. 14394-14405.
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abstract = "Docosahexaenoic acid (DHA) is an ω-3 dietary-derived polyunsaturated fatty acid of marine origin enriched in testes and necessary for normal fertility, yet the mechanisms regulating the enrichment of DHA in the testes remain unclear. Long-chain ACSL6 (acyl-CoA synthetase isoform 6) activates fatty acids for cellular anabolic and catabolic metabolism by ligating a CoA to a fatty acid, is highly expressed in testes, and has high preference for DHA. Here, we investigated the role of ACSL6 for DHA enrichment in the testes and its requirement for male fertility. Acsl6-/- males were severely subfertile with smaller testes, reduced cauda epididymal sperm counts, germ cell loss, and disorganization of the seminiferous epithelium. Total fatty acid profiling of Acsl6-/- testes revealed reduced DHA and increasedω-6 arachidonic acid, a fatty acid profile also reflected in phospholipid composition. Strikingly, lipid imaging demonstrated spatial redistribution of phospholipids in Acsl6-/- testes. Arachidonic acid-containing phospholipids were predominantly interstitial in control testes but diffusely localized across Acsl6-/- testes. In control testes, DHA-containing phospholipids were predominantly within seminiferous tubules, which contain Sertoli cells and spermatogenic cells but relocalized to the interstitium in Acsl6-/- testes. Taken together, these data demonstrate that ACSL6 is an initial driving force for germ cell DHA enrichment and is required for normal spermatogenesis and male fertility.",
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AU - Fernandez, Regina F.

AU - Kim, Sora Q.

AU - Diaz, Victoria D.

AU - Jackson, Shelley N.

AU - Liu, Lei

AU - Brenna, James T

AU - Hermann, Brian P.

AU - Geyer, Christopher B.

AU - Ellis, Jessica M.

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AB - Docosahexaenoic acid (DHA) is an ω-3 dietary-derived polyunsaturated fatty acid of marine origin enriched in testes and necessary for normal fertility, yet the mechanisms regulating the enrichment of DHA in the testes remain unclear. Long-chain ACSL6 (acyl-CoA synthetase isoform 6) activates fatty acids for cellular anabolic and catabolic metabolism by ligating a CoA to a fatty acid, is highly expressed in testes, and has high preference for DHA. Here, we investigated the role of ACSL6 for DHA enrichment in the testes and its requirement for male fertility. Acsl6-/- males were severely subfertile with smaller testes, reduced cauda epididymal sperm counts, germ cell loss, and disorganization of the seminiferous epithelium. Total fatty acid profiling of Acsl6-/- testes revealed reduced DHA and increasedω-6 arachidonic acid, a fatty acid profile also reflected in phospholipid composition. Strikingly, lipid imaging demonstrated spatial redistribution of phospholipids in Acsl6-/- testes. Arachidonic acid-containing phospholipids were predominantly interstitial in control testes but diffusely localized across Acsl6-/- testes. In control testes, DHA-containing phospholipids were predominantly within seminiferous tubules, which contain Sertoli cells and spermatogenic cells but relocalized to the interstitium in Acsl6-/- testes. Taken together, these data demonstrate that ACSL6 is an initial driving force for germ cell DHA enrichment and is required for normal spermatogenesis and male fertility.

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