Abstract：
: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.
journal_name
J Lipid Resjournal_title
Journal of lipid researchauthors
Blackburn NB,Michael LF,Meikle PJ,Peralta JM,Mosior M,McAhren S,Bui HH,Bellinger MA,Giles C,Kumar S,Leandro AC,Almeida M,Weir JM,Mahaney MC,Dyer TD,Almasy L,VandeBerg JL,Williams-Blangero S,Glahn DC,Duggirala R,Kodoi
10.1194/jlr.P094433subject
Has Abstractpub_date
2019-09-01 00:00:00pages
1630-1639issue
9eissn
0022-2275issn
1539-7262pii
jlr.P094433journal_volume
60pub_type
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journal_title：Journal of lipid research
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journal_title：Journal of lipid research
pub_type： 杂志文章
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journal_title：Journal of lipid research
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journal_title：Journal of lipid research
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doi：10.1194/jlr.E046334
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pub_type： 杂志文章
doi：10.1194/jlr.M600136-JLR200
更新日期：2006-11-01 00:00:00
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1999-06-01 00:00:00
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1993-04-01 00:00:00
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1980-01-01 00:00:00
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1976-01-01 00:00:00
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1990-07-01 00:00:00
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.M800551-JLR200
更新日期：2009-05-01 00:00:00
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1971-07-01 00:00:00
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1984-10-01 00:00:00
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pub_type： 杂志文章,评审
doi：10.1194/jlr.R008896
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
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pub_type： 临床试验,杂志文章
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journal_title：Journal of lipid research
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doi：
更新日期：1987-08-01 00:00:00
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pub_type： 杂志文章
doi：10.1194/jlr.M089714
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.M400064-JLR200
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1997-07-01 00:00:00
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1983-04-01 00:00:00
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.C500010-JLR200
更新日期：2005-08-01 00:00:00
abstract：:Sonication of rat fat cells caused an increase in lipolysis in the absence of lipolytic stimulants (basal lipolysis) and loss of epinephrine responsiveness. Sonication of endogenous lipid droplets from fat cells also induced an increase in lipolysis in the presence of hormone-sensitive lipase (HSL) and loss of epineph...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1994-01-01 00:00:00
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pub_type： 杂志文章
doi：10.1194/jlr.M500294-JLR200
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