Tanno Honoka, Sassa Takayuki, Sawai Megumi, Kihara Akio
Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Jan;1866(1):158842. doi: 10.1016/j.bbalip.2020.158842. Epub 2020 Oct 16.
Although most mammalian fatty acids (FAs) are straight-chain, there also exist branched-chain FAs such as iso- and anteiso-FAs, especially in the meibomian glands. Meibum lipids, which are secreted from the meibomian glands and are important for dry eye prevention, contain abundant branched-chain lipids, such as cholesteryl esters and wax esters with chain-lengths of ≥C21 (very-long-chain; VLC). However, the exact tissue distribution of branched-chain lipids or the enzymes involved in the production of branched-chain VLCFAs has remained poorly understood. Here, we revealed that FA elongases ELOVL1, ELOVL3, and ELOVL7, of the seven mammalian ELOVL isozymes, elongated saturated branched-chain acyl-CoAs. ELOVL3 was highly active toward iso-C17:0 and anteiso-C17:0 acyl-CoAs and elongated them up to iso-C23:0 and anteiso-C25:0 acyl-CoAs, respectively. ELOVL1 elongated both iso- and anteiso-C23:0 acyl-CoAs to C25:0 acyl-CoAs. By establishing a liquid chromatography-tandem mass spectrometry method capable of separating branched- and straight-chain lipids, we showed that essentially all of the cholesteryl esters and 88% of the wax esters in the mouse meibomian glands are branched. In Elovl1 mutant mice, the levels of ≥C24:0 branched-chain cholesteryl esters and ≥C25:0 branched-chain wax esters were decreased, indicating that ELOVL1 indeed elongates branched-chain VLC acyl-CoAs in vivo. In addition, substantial amounts of ceramides containing branched-chain FAs were present in the skin, meibomian glands, and liver. Our findings provide new insights into the molecular mechanisms that create FA and lipid diversity.
尽管大多数哺乳动物脂肪酸（FAs）是直链的，但也存在支链脂肪酸，如异脂肪酸和反异脂肪酸，尤其是在睑板腺中。睑脂由睑板腺分泌，对预防干眼症很重要，其中含有丰富的支链脂质，如链长≥C21的胆固醇酯和蜡酯（超长链；VLC）。然而，支链脂质的确切组织分布或参与支链超长链脂肪酸（VLCFAs）产生的酶仍知之甚少。在这里，我们发现，在七种哺乳动物ELOVL同工酶中，脂肪酸延长酶ELOVL1、ELOVL3和ELOVL7可延长饱和支链酰基辅酶A。ELOVL3对异-C17:0和反异-C17:0酰基辅酶A具有高活性，并分别将它们延长至异-C23:0和反异-C25:0酰基辅酶A。ELOVL1将异-C23:0和反异-C23:0酰基辅酶A都延长至C25:0酰基辅酶A。通过建立一种能够分离支链和直链脂质的液相色谱-串联质谱方法，我们发现小鼠睑板腺中基本上所有的胆固醇酯和88%的蜡酯都是支链的。在Elovl1突变小鼠中，≥C24:0支链胆固醇酯和≥C25:0支链蜡酯的水平降低，表明ELOVL1确实在体内延长支链VLC酰基辅酶A。此外，皮肤、睑板腺和肝脏中存在大量含有支链脂肪酸的神经酰胺。我们的发现为产生脂肪酸和脂质多样性的分子机制提供了新的见解。
