ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-10, Vol.107 (43), p.18439-18444
• Main Authors: Ohno, Yusuke, Suto, Shota, Yamanaka, Masao, Mizutani, Yukiko, Mitsutake, Susumu, Igarashi, Yasuyuki, Sassa, Takayuki, Kihara, Akio, Holthuis, Joost
• Format: Article
• Language: English
• Subjects: Acetyltransferases - antagonists & inhibitors; Acetyltransferases - genetics; Acetyltransferases - metabolism; Acyl Coenzyme A - biosynthesis; Acyl Coenzyme A - chemistry; Base Sequence; Biological Sciences; Cell Line; Ceramides; DNA Primers - genetics; Enzymes; Fatty acids; Fatty Acids - biosynthesis; Fatty Acids - chemistry; Female; Gene Knockdown Techniques; HeLa Cells; Humans; In Vitro Techniques; Kinases; Lipids; Male; Mammals; Membrane Microdomains - metabolism; Membrane Proteins - metabolism; Membranes; Messenger RNA; Protein synthesis; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Small interfering RNA; Sphingolipids; Sphingolipids - biosynthesis; Sphingolipids - chemistry; Sphingosine N-Acyltransferase - metabolism; Studies; Substrate Specificity; Tissue Distribution; Tumor Suppressor Proteins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1005572107

Very long-chain fatty acids (VLCFAs) exert a variety of cellular functions and are associated with numerous diseases. However, the precise pathway behind their elongation has remained elusive. Moreover, few regulatory mechanisms for VLCFAs synthesis have been identified. Elongases catalyze the first of four steps in the VLCFA elongation cycle; mammals have seven elongases (ELOVL1–7). In the present study, we determined the precise substrate specificities of all the ELOVLs by in vitro analyses. Particularly notable was the high activity exhibited by ELOVL1 toward saturated and monounsaturated C20- and C22-CoAs, and that it was essential for the production of C24 sphingolipids, which are unique in their capacity to interdigitate within the membrane as a result of their long chain length. We further established that ELOVL1 activity is regulated with the ceramide synthase CERS2, an enzyme essential for C24 sphingolipid synthesis. This regulation may ensure that the production of C24-CoA by elongation is coordinated with its utilization. Finally, knockdown of ELOVL1 caused a reduction in the activity of the Src kinase LYN, confirming that C24-sphingolipids are particularly important in membrane microdomain function.