期刊
JOURNAL OF LIPID RESEARCH
卷 60, 期 9, 页码 1630-1639出版社
ELSEVIER
DOI: 10.1194/jlr.P094433
关键词
lipidomics; sphingolipids; genomics; genetics
资金
- National Institutes of Health (NIH) [P01 HL045522, R01 HL113323, R01 HL140681, R37 MH059490]
- NIH T2D-GENES Consortium [U01 DK085524, U01 DK085584, U01 DK085501, U01 DK085526, U01 DK085545]
- NIH [C06 RR020547]
- National Health and Medical Research Council of Australia Senior Research Fellowship [APP1042095]
The de novo ceramide synthesis pathway is essential to human biology and health, but genetic influences remain unexplored. The core function of this pathway is the generation of biologically active ceramide from its precursor, dihydroceramide. Dihydroceramides have diverse, often protective, biological roles; conversely, increased ceramide levels are biomarkers of complex disease. To explore the genetics of the ceramide synthesis pathway, we searched for deleterious nonsynonymous variants in the genomes of 1,020 Mexican Americans from extended pedigrees. We identified a Hispanic ancestry-specific rare functional variant, L175Q, in delta 4-desaturase, sphingolipid 1 (DEGS1), a key enzyme in the pathway that converts dihydroceramide to ceramide. This amino acid change was significantly associated with large increases in plasma dihydroceramides. Indexes of DEGS1 enzymatic activity were dramatically reduced in heterozygotes. CRISPR/Cas9 genome editing of HepG2 cells confirmed that the L175Q variant results in a partial loss of function for the DEGS1 enzyme. Understanding the biological role of DEGS1 variants, such as L175Q, in ceramide synthesis may improve the understanding of metabolic-related disorders and spur ongoing research of drug targets along this pathway.
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