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

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

Sea lions develop human-like vernix caseosa delivering branched fats and squalene to the GI tract

Vernix caseosa, the white waxy coating found on newborn human skin, is thought to be a uniquely human substance. Its signature characteristic is exceptional richness in saturated branched chain fatty acids (BCFA) and squalene. Vernix particles sloughed from the skin suspended in amniotic fluid are swallowed by the human fetus, depositing BCFA/squalene throughout the gastrointestinal (GI) tract, thereby establishing a unique microbial niche that influences development of nascent microbiota. Here we show that late-term California sea lion (Zalophus californianus) fetuses have true vernix caseosa, delivering BCFA and squalene to the fetal GI tract thereby recapitulating the human fetal gut microbial niche. These are the first data demonstrating the production of true vernix caseosa in a species other than Homo sapiens. Its presence in a marine mammal supports the hypothesis of an aquatic habituation period in the evolution of modern humans

ARDD 2020: from aging mechanisms to interventions

Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7th Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8th ARDD meeting that is scheduled for the 31st of August to 3rd of September, 2021, at Columbia University, USA

Dietary fat intakes for pregnant and lactating women.

Dietary fat intake in pregnancy and lactation affects pregnancy outcomes and child growth, development and health. The European Commission charged the research project PERILIP, jointly with the Early Nutrition Programming Project, to develop recommendations on dietary fat intake in pregnancy and lactation. Literature reviews were performed and a consensus conference held with international experts in the field, including representatives of international scientific associations. The adopted conclusions include: dietary fat intake in pregnancy and lactation (energy%) should be as recommended for the general population; pregnant and lactating women should aim to achieve an average dietary intake of at least 200 mg DHA/d; intakes of up to 1 g/d DHA or 2.7 g/d n-3 long-chain PUFA have been used in randomized clinical trials without significant adverse effects; women of childbearing age should aim to consume one to two portions of sea fish per week, including oily fish; intake of the DHA precursor, alpha-linolenic acid, is far less effective with regard to DHA deposition in fetal brain than preformed DHA; intake of fish or other sources of long-chain n-3 fatty acids results in a slightly longer pregnancy duration; dietary inadequacies should be screened for during pregnancy and individual counselling be offered if needed

Examination of the kinetic isotopic effect to the acetylation derivatization for the gas chromatographic-combustion-isotope ratio mass spectrometric doping control analysis of endogenous steroids

In gas chromatographic-combustion-isotope ratio mass spectrometry (GC-C-IRMS) doping control analysis, endogenous androgenic anabolic steroids and their metabolites are commonly acetylated using acetic anhydride reagent, thus incorporating exogenous carbon that contributes to the measured isotope ratio. Comparison of the endogenous δ13C of free, mono-, and di-acetylated steroids requires application of corrections, typically through straightforward use of the mass balance equation. Variability in kinetic isotope effects (KIE) due to steroid structures could cause fractionation of endogenous steroid carbon, resulting in inaccurate results. To test for possible KIE influence on δ13C, acetic anhydride of graded isotope ratio within the natural abundance range was used under normal derivatization conditions to test for linearity. In all cases, plots of measured steroid acetate δ13C versus acetic anhydride δ13C were linear and slopes were not significantly different. Regression analysis of the Δδ13C of enriched acetic anhydrides versus Δδ13C of derivatized steroids shows that KIE are similar in all cases. We conclude that δ13C calculated from the mass balance equation is independent of the δ13C of the acetic anhydride reagent, and that net KIE under normal derivatization conditions do not bias the final reported steroid δ13C. © 2012 John Wiley & Sons, Ltd

External calibration in Gas Chromatography-Combustion-Isotope Ratio Mass Spectrometry measurements of endogenous androgenic anabolic steroids in sports doping control

An alternative calibration procedure for the Gas Chromatography-Combustion-Isotope Ratio Mass Spectrometry (GC-C-IRMS) measurements of the World Antidoping Agency (WADA) Accredited Laboratories is presented. To alleviate the need for externally calibrated CO2 gas for GC-C-IRMS analysis of urinary steroid metabolites, calibration using an external standard mixture solution of steroids with certified isotopic composition was investigated. The reference steroids of the calibration mixture and routine samples underwent identical instrumental processes. The calibration standards bracketed the entire range of the relevant δ13C values for the endogenous and exogenous steroids as well as their chromatographic retention times. The certified δ13C values of the reference calibrators were plotted in relation to measured m/z 13CO2/12CO2 (i.e. R(45/44)) mass spectrometric signals of each calibrator. δ13C values of the sample steroids were calculated from the least squares fit through the calibration curve. The effect of the external calibration on δ13C values, using the same calibration standards and set of urine samples but different brands of GC-C-IRMS instruments, was assessed by an interlaboratory study in the WADA Accredited Laboratories of Sydney, Australia and Athens, Greece. Relative correspondence between the laboratories for determination of androsterone, etiocholanolone, 5β-androstane-3α,17β-diacetate, and pregnanediacetate means were SD(δ13C)=0.12‰, 0.58‰, -0.34‰, and -0.40‰, respectively. These data demonstrate that accurate intralaboratory external calibration with certified steroids provided by United States Antidoping Agency (USADA) and without external CO2 calibration is feasible and directly applicable to the WADA Accredited Laboratories for the harmonization of the GC-C-IRMS measurements. © 2011 Elsevier B.V

Higher efficacy of dietary DHA provided as a phospholipid than as a triglyceride for brain DHA accretion in neonatal piglets

Long-chain PUFAs (LCPUFAs) occur in foods primarily in the natural lipid classes, triacylglycerols (TAGs) or phospholipids (PLs). We studied the relative efficacy of the neural omega-3 DHA provided in formula to growing piglets as a dose of 13C-DHA bound to either TAG or phosphatidylcholine (PC). Piglets were assigned to identical formula-based diets from early life and provided with TAG-13C-DHA or PC-13C-DHA orally at 16 days. Days later, piglet organs were analyzed for 13C-DHA and other FA metabolites. PC-13C-DHA was 1.9-fold more efficacious for brain gray matter DHA accretion than TAG-13C-DHA, and was similarly more efficacious in gray matter synaptosomes, retina, liver, and red blood cells (RBCs). Liver labeling was greatest, implying initial processing in that organ followed by export to other organs, and suggesting that transfer from gut to bloodstream to liver in part drove the difference in relative efficacy for tissue accretion. Apparent retroconversion to 22:5n-3 was more than double for PC-13C-DHA and was more prominent in neural tissue than in liver or RBCs. These data directly support greater efficacy for PC as a carrier for LCPUFAs compared with TAG, consistent with previous studies of arachidonic acid and DHA measured in other species. Copyright \ua9 2014 by the American Society for Biochemistry and Molecular Biology, Inc.Peer reviewed: YesNRC publication: Ye

The ER-Associated Degradation Adapter Protein Sel1L Regulates Triglyceride Metabolism via Lipoprotein Lipase

Sel1L is an adaptor protein for the E3 ligase Hrd1 in the endoplasmic reticulum-associated degradation (ERAD), but its physiological role in a cell-type-specific manner remains unclear. Here we show that mice with adipocyte-specific Sel1L deficiency are resistant to diet-induced obesity and exhibit postprandial hypertriglyceridemia. Mechanistically, our data demonstrate a critical requirement of Sel1L for the secretion of lipoprotein lipase (LPL), independently of its role in Hrd1-mediated ERAD and ER homeostasis. Further biochemical analyses revealed that Sel1L physically interacts and stabilizes the LPL maturation complex consisted of LPL and lipase-maturation factor 1 (LMF1). In the absence of Sel1L, LPL is retained in the ER and prone to the formation of protein aggregates, which are degraded by autophagy-mediated degradation. The Sel1L-mediated control of LPL secretion is seen in other LPL-expressing cell types as well such as cardiac muscle and macrophages. Thus, our study reports a novel role of Sel1L in LPL secretion and systemic lipid metabolism