7. Physiological functions and biosynthesis of ether lipids

Most mammalian lipids consist of fatty acid chains ester-linked to a glycerol backbone. In contrast, some lipids use fatty alcohols as their hydrocarbon chains, forming ether bonds with the glycerol backbone. Such lipids are collectively referred to as ether lipids. Ether bonds are more resistant to hydrolysis than ester bonds, and thus exhibit greater chemical stability. Given that lipids in archaea, which often inhabit extreme environments, are predominantly ether lipids, the high chemical stability of ether lipids is thought to allow them to remain stable across a wide range of environmental conditions. However, their resistance to degradation through hydrolysis may be disadvantageous from the standpoint of maintaining homeostasis through a balance between synthesis and degradation. The presence of ether lipids in biological systems nevertheless strongly suggests that they possess functions based on their high chemical stability that cannot be replaced by ester-type lipids. However, the physiological significance of ether lipids and the molecular mechanisms by which they regulate biological functions remain largely unclear.

In mammals, ether lipids include plasmalogens (plasmenylcholines and plasmenylethanolamines), their plasmanyl counterparts, platelet-activating factors (PAFs), alkyl diacylglycerols, alkyl triacylglycerols, GPI anchors, and seminolipids (Figure 18A). Among these, plasmalogens are the most abundant, accounting for approximately 15–20% of membrane phospholipids, and are particularly enriched in the brain (myelin), heart, and skeletal muscle. Mutations in genes involved in plasmalogen biosynthesis cause rhizomelic chondrodysplasia punctata, which is characterized by proximal limb shortening, congenital cataracts, and severe developmental delay, thereby highlighting the physiological importance of plasmalogens.

Differences in the roles of FAR1 and FAR2 in fatty alcohol production

Our laboratory initially focused on fatty acyl-CoA reductases FAR1 and FAR2 during studies on meibum lipids, and subsequently investigated their substrate specificities and generated and analyzed knockout (KO) mice. As described in “Section 5: Prevention of dry eye by meibum lipids”, FAR1 and FAR2 are involved primarily in the production of long-chain (≤C20) and very-long-chain (≥C21) fatty alcohols, respectively¹⁾ (Figure 18B). Far2 KO mice exhibit dry eye, and in their meibum lipids, wax monoesters containing very-long-chain fatty alcohols as well as type 1ω-, type 2α-, and type 2ω-wax diesters are almost absent¹⁾. In contrast, in Far1 KO mice, the production of ether lipids, including plasmalogens and seminolipids, is impaired, and these mice exhibit hypomyelination, delayed bone ossification, and impaired spermatogenesis (see below).

Role of FAR1 in plasmalogen production

Because the fatty alcohol moieties of most ether lipids are predominantly long-chain, ether lipid levels are markedly reduced in Far1 KO mice, whereas they are largely unaffected in Far2 KO mice. For example, in the brains of Far1 KO mice, the levels of plasmenylethanolamines are reduced to 8% of those in wild-type mice, concomitant with an increase in diacyl-type phosphatidylethanolamines²⁾. Most Far1 KO mice do not survive to adulthood and exhibit hypomyelination as well as impaired bone ossification during embryonic development²⁾.

Identification of DHRS7 as a novel alkylglycerone phosphate reductase in ether lipid biosynthesis

DHRS7B had previously been known as an alkylglycerone phosphate reductase responsible for the third step of ether lipid biosynthesis. Our laboratory subsequently identified DHRS7 as a novel alkylglycerone phosphate reductase³⁾. While DHRS7B is primarily localized in peroxisomes, DHRS7 is localized in the endoplasmic reticulum. In addition, the two enzymes contribute to the production of distinct fatty acid species in plasmalogens. DHRS7 contributes most strongly to the production of C18:1 species, followed by C16:0 and C22:6 species, whereas DHRS7B contributes to the production of a wide range of species³⁾.

Seminolipids in spermatogenesis

Seminolipids are testis-specific ether glycolipids that are known to play essential roles in spermatogenesis. However, the molecular diversity of the alkyl and acyl moieties in seminolipids, the stage of spermatogenesis at which they are produced, and the FAR isozyme (FAR1 or FAR2) responsible for the synthesis of the alkyl moiety have remained largely unclear. To address these issues, we analyzed Far1 KO mice.

Far1 is expressed in spermatogonia, spermatocytes, and spermatids, and male Far1 KO mice are infertile⁴⁾. In these mice, sperms are absent in the epididymides, the testes are reduced in size, and multinucleated cells and vacuoles are present in the seminiferous tubules. In wild-type mouse testes, more than 90% of seminolipids are composed of species containing C16:0 in both the alkyl and acyl moieties, and these seminolipids are present in all spermatogenic cell types. In contrast, seminolipids are completely absent in Far1 KO mice, and instead, non-ether, diacyl-type sulfogalactosyl diacylglycerols are produced. These findings indicate that FAR1 is essential for seminolipid synthesis and normal spermatogenesis.

Conclusion

In summary, our laboratory has elucidated the distinct roles of FAR1 and FAR2 (Figure 18B), characterized the species of seminolipids, and identified a novel enzyme in the ether lipid biosynthetic pathway. These findings suggest that ether lipids play important roles in regulating biological functions in a class- and molecular species–specific manner.

References

1. Otsuka K, Sawai-Ogawa M, Kihara A. (2022) Formation of fatty alcohols—components of meibum lipids—by the fatty acyl-CoA reductase FAR2 is essential for dry eye prevention. FASEB J, 36, e22216.
2. Takahashi T, Otsuka K, Sassa T, Kihara A. (2025) Acyl-CoA reductase Far1 deficiency impairs ether lipid production and hypomyelination in mouse brains. Mol Cell Biol, 45, 495–510.
3. Takahashi T, Otsuka K, Sassa T, Kihara A. (2026) The acyl- and alkyl-glycerone phosphate reductase DHRS7 is involved in the production of distinct plasmalogen species from DHRS7B. J Cell Sci, 139, jcs264759 (Featured as a Research Highlight in J Cell Sci).
4. Tamazawa A, Naganuma T, Otsuka K, Takahashi T, Sassa T, Kihara A. (2025) Fatty acyl-CoA reductase FAR1 is essential for the testicular seminolipid synthesis required for spermatogenesis and male fertility. J Biol Chem, 301, 108538.