Fads3 modulates docosahexaenoic acid in liver and brain

Zhang, Ji Yao; Qin, Xia; Liang, Allison; Kim, Ellen; Lawrence, Peter; Park, Woo Jung; Kothapalli, Kumar S.D.; Brenna, J. Thomas

doi:10.1016/j.plefa.2017.07.001

Cited by 24 publications

(26 citation statements)

References 55 publications

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“…Although Fads3 KO mice have previously been generated, only results of limited phenotypic analyses have been reported. 48 In that report, no differences were observed between wild-type and Fads3 KO mice in body weight up to Day 60 after birth, or in brain weight up to Day 30 after birth. However, the comprehensive knockout mouse phenotypic analysis project conducted by the International Mouse Phenotyping Consortium (https ://www.mouse pheno type.org) has shown some phenotypes of Fads3 KO mice, such as decreased circulating phosphate levels, absence of pinna reflex, and auditory abnormalities.…”

Section: Discussionmentioning

confidence: 82%

“…In another report, Fads3 KO mice were created and various PUFA species were measured in the KO mouse brain and liver, based on the prediction that FADS3 would act as FA desaturase. 48 However, differences in PUFA levels between wild-type and Fads3 KO mice were very small. In that report, Δ11,13-C18:2 FA was not detected in the liver or heart of either wild-type or Fads3 KO mice administered with trans-vaccenic acid.…”

Section: Discussionmentioning

confidence: 99%

“…Although it has been reported to introduce a cis double bond between C13 and C14 of trans-vaccenic acid (∆11-C18:1), 47 there is also a contradictory report. 47,48 To further confirm the involvement of FADS3 in SPD biosynthesis, we constructed FADS3 KO HAP1 cells, a near-haploid cell line derived from human chronic myelogenous leukemia. We obtained two FADS3 KO clones (KO1 and KO2), which lack 480 bp and 28 bp, respectively, around exon 1 of the FADS3 gene ( Figure 6C).…”

Section: Involvement Of Fads3 In Spd Ceramide Biosynthesismentioning

confidence: 99%

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Biosynthesis of the anti‐lipid‐microdomain sphingoid base 4,14‐sphingadiene by the ceramide desaturase FADS3

et al. 2020

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Sphingolipids are multifunctional lipids. Among the sphingolipid-component sphingoid bases, 4,14-sphingadiene (SPD) is unique such that it has a cis double bond with a bent structure. Although SPD was discovered half a century ago, its tissue distribution, biosynthesis, and degradation remain poorly understood. Here, we established a specific and quantitative method for SPD measurement and found that SPD exists in a wide range of mammalian tissues. SPD was especially abundant in kidney, where the amount of SPD was ~2/3 of sphingosine, the most abundant sphingoid base in mammals. Although SPD is metabolized to ceramides and SPD 1-phosphate with almost the same efficiency as sphingosine, it is less susceptible to degradation by a cleavage reaction, at least in vitro. We identified the fatty acid desaturase family protein FADS3 as a ceramide desaturase that produces SPD ceramides by desaturating ceramides containing sphingosine. SPD sphingolipids were preferentially localized outside lipid microdomains, suggesting that SPD has different functions compared to other sphingoid bases in the formation of lipid microdomains. In summary, we revealed the biosynthesis and degradation pathways of SPD and its characteristic membrane localization. Our findings contribute to the elucidation of the molecular mechanism underlying the generation of sphingolipid diversity. K E Y W O R D S4,14-sphingadiene, ceramide, fatty acid desaturase, lipid, sphingolipid How to cite this article: Jojima K, Edagawa M, Sawai M, Ohno Y, Kihara A. Biosynthesis of the anti-lipid-microdomain sphingoid base 4,14-sphingadiene by the ceramide desaturase FADS3. The FASEB Journal. 2020;34:3318-3335.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Involvement Of Fads3 In Spd Ceramide Biosynthesismentioning

confidence: 99%

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Biosynthesis of the anti‐lipid‐microdomain sphingoid base 4,14‐sphingadiene by the ceramide desaturase FADS3

et al. 2020

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“…S4). Finally, we analyzed the LCB profile in plasma of FADS3deficient mice (14). No d18:2 was detected in plasma of FADS Ϫ/Ϫ mice, whereas FADS ϩ/Ϫ mice had about 50% of the WT levels ( Fig.…”

Section: Resultsmentioning

confidence: 99%

FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome

Karsai

Lone

Kutalik

et al. 2020

Journal of Biological Chemistry

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Sphingolipids (SLs) are structurally diverse lipids that are defined by the presence of a long-chain base (LCB) backbone. Typically, LCBs contain a single Δ4E double bond (DB) (mostly d18:1), whereas the dienic LCB sphingadienine (d18:2) contains a second DB at the Δ14Z position. The enzyme introducing the Δ14Z DB is unknown. We analyzed the LCB plasma profile in a gender-, age-, and BMI-matched subgroup of the CoLaus cohort (n = 658). Sphingadienine levels showed a significant association with gender, being on average ∼30% higher in females. A genome-wide association study (GWAS) revealed variants in the fatty acid desaturase 3 (FADS3) gene to be significantly associated with the plasma d18:2/d18:1 ratio (p = −log 7.9). Metabolic labeling assays, FADS3 overexpression and knockdown approaches, and plasma LCB profiling in FADS3-deficient mice confirmed that FADS3 is a bona fide LCB desaturase and required for the introduction of the Δ14Z double bond. Moreover, we showed that FADS3 is required for the conversion of the atypical cytotoxic 1-deoxysphinganine (1-deoxySA, m18:0) to 1-deoxysphingosine (1-deoxySO, m18:1). HEK293 cells overexpressing FADS3 were more resistant to m18:0 toxicity than WT cells. In summary, using a combination of metabolic profiling and GWAS, we identified FADS3 to be essential for forming Δ14Z DB containing LCBs, such as d18:2 and m18:1. Our results unravel FADS3 as a Δ14Z LCB desaturase, thereby disclosing the last missing enzyme of the SL de novo synthesis pathway.

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“…In contrast, Karsai et al (49) showed that FADS3 can directly desaturate sphingosine in vitro, however inhibiting ceramide synthesis with Fumonisin B1 greatly reduced sphingadiene formation in living cells. Mice lacking FADS3 have reduced brain docosahexaenoic acid levels but were reported to display no major phenotypic abnormalities (56). However the International Mouse Phenotyping Consortium (https://www.mousephenotype.org) (57) report impaired auditory response, decreased circulating phosphates, and increased serum albumin in FADS3 knockout mice.…”

Section: Discussionmentioning

confidence: 99%

A novel function of sphingosine kinase 2 in the metabolism of sphinga-4,14-diene lipids

Couttas

Rustam

Song

et al. 2020

Preprint

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Abbreviations: CID: collision induced dissociation; HexCer: hexosylceramide; LC-MS/MS: liquid chromatography-tandem mass spectrometry; SM: sphingomyelin; SphK1: sphingosine kinase 1; SphK2: sphingosine kinase 2; UVPD: ultraviolet photodissociation. AbstractThe number, position, and configuration of double bonds in lipid acyl chains affects membrane packing, fluidity, and recruitment of signalling proteins. Studies on mammalian sphingolipids have focused on those with a saturated sphinganine or mono-unsaturated sphingosine long chain base. Sphingolipids with a diunsaturated sphingadiene base have been reported but are poorly characterised. Employing high-resolution untargeted mass spectrometry, we observed marked accumulation of lipids containing a sphingadiene base, but not those with a more common sphingosine backbone, in the hippocampus of mice lacking the metabolic enzyme sphingosine kinase 2 (SphK2). Applying ultraviolet photodissociation tandem mass spectrometry (UVPD-MS/MS) the double bonds were confidently assigned to the C4-C5 and C14-C15 positions of the sphingoid base. Sphingosine kinases are involved in lysosomal catabolism of all sphingolipids, producing sphingoid base phosphates that are irreversibly degraded by sphingosine 1-phosphate lyase. Both SphK1 and SphK2 phosphorylated sphinga-4,14-diene as efficiently as sphingosine, however deuterated tracer experiments demonstrated that ceramides with a sphingosine base are more rapidly metabolised in cultured cells than those with a sphingadiene base. SphK2 silencing significantly impeded the catabolism of both sphingosine-and sphingadiene-based sphingolipids. Since SphK2 is the dominant sphingosine kinase in brain, we propose that accumulation of sphingadiene lipids in SphK2-deficient brains results from the intrinsically slower catabolism of sphingadiene lipids, combined with a bottleneck in the catabolic pathway created by the absence of SphK2. We speculate that accumulation of these lipids in the absence of SphK2 function may affect the fluidity and signalling properties of cell membranes.

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Fads3 modulates docosahexaenoic acid in liver and brain

Cited by 24 publications

References 55 publications

Biosynthesis of the anti‐lipid‐microdomain sphingoid base 4,14‐sphingadiene by the ceramide desaturase FADS3

Biosynthesis of the anti‐lipid‐microdomain sphingoid base 4,14‐sphingadiene by the ceramide desaturase FADS3

FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome

A novel function of sphingosine kinase 2 in the metabolism of sphinga-4,14-diene lipids

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