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Docosahexaenoic acid [22:6(n-3), DHA] plays an important role in human physiology including gut health. This research aimed to investigate the impact of positional distribution of DHA in dietary triacylglycerols (TAG) on gut metabolomic profile and microbiota. In the 4-week feeding trial, the Sprague-Dawley rats were fed on an n-3 deficient feed supplemented with TAG containing DHA at the sn -1, 2, or 3 position and palmitic acid at the remaining positions. Three groups receiving standard n-3 adequate feed, n-3 deficient feed, or n-3 deficient feed supplemented with tripalmitin were included as controls. The gut metabolome was studied using LC–MS-based non-targeted metabolomics, and microbiota profiles were investigated by 16S rRNA sequencing. Compared to the n-3 adequate diet, four-week feeding on the n-3 deficient diet affected the fecal pyrimidine metabolism, steroid biosynthesis, and arginine and proline metabolism. Feeding with DHA-containing TAGs, especially TAG with DHA at sn -3 position, increased the level of N5-Carboxy aminoimidazole ribonucleotide related to purine biosynthesis and dimethylbenzimidazole involved in vitamin B2 biosynthesis. N-3 deficient diet lowered the abundance of the genus Alistipes and the species Bacteroides massiliensis in the gut microbiota. Compared to the n-3 deficient groups, feeding with DHA-containing TAGs decreased the abundance of species Prevotella sp. CAG: 1031, and feeding with sn -2 DHA resulted in an increase in the abundance of Bacteroides fragilis and a decrease in the abundance of Faecalibacterium sp. CAP 74. This is the first study showing that dietary DHA from different positions of TAG may affect gut metabolites and microbiota differently. [ABSTRACT FROM AUTHOR]

Abstract: A novel approach has been developed for activating the highly bioactive long-chain n-3 polyunsaturated fatty acids EPA and DHA as oxime esters and incorporating them exclusively to the end-positions of glycerol and enantiopure 1-O-alkylglycerols. The Candida antarctica lipase B was observed to display a superb regioselectivity when using the acetoxime esters of EPA and DHA as acyldonors under mild condition to keep acyl-migration side-reaction under complete control. Regiopure 1,3-diacylglycerols, 1-O-alkyl-3-acyl-sn-glycerols and their antipodes possessing EPA and DHA were afforded in very high purity and yields. [Copyright &y& Elsevier]

Abstract: The naturally occurring 1-O-alkyl-sn-glycerols and their methoxylated congeners, 1-O-(2′-methoxyalkyl)-sn-glycerols, are biologically active compounds, ubiquitously found in nature as diacyl glyceryl ether lipids and phosphoether lipids. The chief objective of this article is to provide a comprehensive and up to date review on such ether lipids. The occurrence and distribution of these compounds in nature are extensively reviewed, their chemical structure and molecular variety, their biosynthesis and chemical synthesis and, finally, their various biological effects are described and discussed. An unprecedented biosynthesis of the 2′-methoxylated alkylglycerols is proposed. The first synthesis of enantiopure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol, the most prevalent 2′-methoxylated type alkylglycerol present in cartilaginous fish, is described. It was accomplished by a highly convergent five step process. [Copyright &y& Elsevier]

Abstract: Synthesis of enantiopure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol 1, the principal methoxylated glyceryl ether found in Nature, is described by a highly convergent five-step process taking place in 27% overall yield. The synthesis is based on an ether bond formation between the chiral synthon (R)-2,3-O-isopropylidene-sn-glycerol and (Z)-(R)-1-chlorohexadec-4-en-2-ol employing ground potassium hydroxide and tetra-n-butylammonium bromide as a catalyst under solvent free conditions. [ABSTRACT FROM AUTHOR]

Abstract: Synthesis of symmetrically structured triacylglycerols possessing bioactive n−3 polyunsaturated fatty acids (eicosapentaenoic acid or docosahexaenoic acid) at the 2-position and a short-chain fatty acid (C2, C4, C6) located at the end-positions by a highly efficient two-step chemoenzymatic process is described. Full regiocontrol devoid of any acyl-migration side reactions was obtained in both a lipase promoted step to introduce the short-chain fatty acids exclusively into the primary alcohol positions of glycerol using activated vinyl esters at low temperature and a subsequent coupling reaction involving free EPA and DHA using EDAC as a coupling agent. [Copyright &y& Elsevier]

Abstract: A highly efficient two-step chemoenzymatic synthesis of enantiopure structured ether lipids of the 1-O-alkyl-2,3-diacyl-sn-glycerol type has been developed. Chimyl, batyl and selachyl alcohols possessing pure saturated fatty acid (SFA) attached to the sn-3 position and pure EPA and DHA attached to the sn-2 position were obtained under full regiocontrol. This was offered by mild conditions and a highly efficient lipase that operated at room temperature. High-resolution 1H NMR spectroscopy was used to monitor the progress of the reactions and to evaluate the full regiocontrol of the reactions involved by keeping track of all prospective adducts involved in these reactions. This was extended to preparation of a focused library of eight monoacyl intermediate adducts for all even-numbered SFA ranging from C2–C16 and the corresponding EPA and DHA structured diacyl glycerol ethers (DAGE) products for chimyl, batyl and selachyl alcohols, the total of 72 compounds. [Copyright &y& Elsevier]

A highly efficient two-step chemoenzymatic synthesis of structured triacylglycerols comprising a pure n-3 polyunsaturated fatty acid at the mid-position and a pure saturated fatty acid located at the end-positions is described. In the first step an immobilized Candida antarctica lipase was observed to display an excellent regioselectivity toward the end-positions of glycerol at 0–4°C using vinyl esters as acylating agents. The n-3 fatty acids were introduced into the remaining mid-position highly efficient and in excellent yields using EDCI coupling agent. [Copyright &y& Elsevier]

Highlights • DHA was efficiently absorbed in Sprague-Dawley rats with mild n-3 deficiency. • No significant differences in the absorption between DHA in sn -1 and sn -3 positions. • Less fecal DHA from the sn -2 position compared with the sn -1 and sn -3 positions. • 5-Day intervention enough to modify the fatty acid profile of plasma phospholipids. Abstract Lack of synthetic enantiospecific triacylglycerols (TAGs) has hindered our understanding of the impact of TAG structure on the absorption and metabolic fate of fatty acids (FAs). In a five-day feeding trial with mildly (n-3) deficient rats, the bioavailability of docosahexaenoic acid [22:6(n-3), DHA] and stearic acid (18:0) from the two different enantiomers of TAG: sn -22:6(n-3)-18:0-18:0 and sn -18:0-18:0-22:6(n-3), and their regioisomeric TAG: sn -18:0-22:6(n-3)-18:0 was compared. Less secretion of fecal DHA was detected from the sn -2 position compared with the sn -1 and sn -3 positions, but no difference was found in DHA content of the fasting plasma or in the weight of the body or organs. 18:0 was lost to feces mainly as cleaved from the primary positions but also as glycerol-bound. The 5-day intervention in rats was long enough to modify the fatty acid profile of plasma phospholipids. [ABSTRACT FROM AUTHOR]

Abstract Epithelial to mesenchymal transition (EMT) is a developmental event characterized by phenotypic switching from a polarized epithelial phenotype to an unpolarized mesenchymal phenotype. Changes to plasma membrane function accompany EMT yet the differences in lipid composition of cells that have undergone EMT are relatively unexplored. To address this the lipidome of two cell models of EMT in breast epithelial tissue, D492 and HMLE, were analyzed by untargeted LC–MS. Detected masses were identified and their abundance was compared through multivariate statistical analysis. Considerable concordance was observed in eight lipid components between epithelial and mesenchymal cells in both cell models. Specifically, an increase in phosphatidylcholine and triacylglycerol were found to accompany EMT while phosphatidylcholine- and phosphatidylethanolamine plasmalogens, as well as diacylglycerols decreased. The most abundant fatty acid lengths were C16 and C18 but mesenchymal cells had on average shorter and more unsaturated fatty acids. The results are consistent with enhanced cell mobility post EMT and reflect a consequence of oxidative stress pre- and post EMT in breast epithelial tissue. [ABSTRACT FROM AUTHOR]

The report describes the first asymmetric synthesis of three derivatives of methoxylated ether lipids (MELs) of the 1- O -alkyl- sn -glycerol type present in the liver oil of various species of cartilaginous fish, all three possessing eighteen-carbon hydrocarbon chains in their ether entity. Two of them were already known, the saturated C18:0 and the monounsaturated C18:1 n-14 MELs, whereas the third one is a novel monounsaturated C18:1 n-9 MEL. All three were isolated and detected by LC-MS studies of a MEL sample obtained from dogfish and shark liver oil. The structural identity of the novel one was unequivocally confirmed to be the C18:1 n-9 MEL by its total synthesis after comparison based on their MS/MS spectra. Their synthesis made use of our previously described enantiopure isopropylidene-protected glyceryl glycidyl ether diastereomer, a double-C3 building block serving as a head group synthon in synthesis of various types of MELs. They were all obtained in high chemical and stereochemical purity and good overall yields. Asymmetric synthesis of methoxylated ether lipids: Total synthesis of two monounsaturated C18:1 and a saturated C18:0 methoxylated ether lipid derivatives. [Display omitted] • First asymmetric syntheses of three methoxylated ether lipids, C18:1 n-14, C18:1 n-9, and C18:0. • Seven methoxylated ether lipid derivatives isolated and detected in shark liver oil. • Five previously known methoxylated ether lipids detected: C16:1 n-12, C16:0, C18:1 n-14, C18:0 and C22:6 n-3. • A novel C18:1 n-9 methoxylated ether lipid confirmed by total synthesis. • An unknown C18:3 methoxylated ether lipid detected. [ABSTRACT FROM AUTHOR]

• First study on the oxidative stability of DHA in regio- and enantiopure TAGs. • DHA in sn -2 was the most stable structure with or without RRR -α-tocopherol. • Without tocopherol, oxidative stability of DHA in sn -1 and sn- 3 was comparable. • With RRR -α-tocopherol, higher stability of DHA in sn -1 compared to sn -3. • Diastereomeric interactions between RRR -α-tocopherol and DHA in sn -1 is proposed. Docosahexaenoic acid (DHA) is essential for health but easily oxidized. Yet the influence of DHA's exact location (sn -1, sn -2, or sn -3) in triacylglycerols on oxidative stability is currently unknown. This is the first study comparing oxidative stability of DHA in regio- and enantiopure triacylglycerols with or without RRR -α-tocopherol. Headspace solid-phase micro-extraction with gas chromatography–mass spectrometry, liquid chromatography–mass spectrometry, and nuclear magnetic resonance spectroscopy were applied. DHA in sn -2 was the most stable with or without added RRR -α-tocopherol resulting in differences in hydroperoxide formation. Without antioxidant, stability of DHA in sn -1 and sn -3 was mainly similar, with slight tendency towards better stability in sn -3. With RRR -α-tocopherol higher stability in sn -1 compared to sn -3 was observed. This points to diastereomeric interactions between RRR -α-tocopherol and DHA in sn -1. These results are highly relevant for enzymatic restructuring processes of DHA-rich fish or microalgae oil concentrates aimed for food supplements or food fortification. [ABSTRACT FROM AUTHOR]

This report describes synthesis of reversed structured triacylglycerols (TAGs) of the LML type, possessing pure EPA or DHA located at the terminal 1,3-positions of the glycerol backbone along with pure even number saturated fatty acids (C6:0–C16:0) occupying the 2-position. These compounds were synthesized by a two-step chemoenzymatic route involving a highly regioselective immobilized Candida antarctica lipase to incorporate EPA or DHA activated as acetoxime esters exclusively into the 1,3-positions of glycerol. The saturated fatty acyl groups were subsequently introduced to the remaining 2-position by EDCI coupling agent to accomplish the title compounds highly efficiently. This is the first report on reversed structured TAGs possessing the long-chain n-3 polyunsaturated fatty acids. It is anticipated that these novel compounds and their synthetic methodology will find various important uses such as analytical standards, in screening for bioactivity and in the pharmaceutical area as prodrugs. [ABSTRACT FROM AUTHOR]

Enantiomers of racemic triacylglycerol (TAG) mixtures were separated using two chiral HPLC columns with a sample recycling system and a UV detector. A closed system without sample derivatisation enabled separation and identification by using enantiopure reference compounds of eleven racemic TAGs with C12–C22 fatty acids with 0–2 double bonds. The prolonged separation time was compensated for by fewer pretreatment steps. Presence of one saturated and one unsaturated fatty acid in the asymmetric TAG favoured the separation. Enantiomeric resolution, at the same time with stronger retention of TAGs, increased with increasing fatty acid chain length in the sn -1(3) position. Triunsaturated TAGs containing oleic, linoleic or palmitoleic acids did not separate. The elution order of enantiomers was determined by chemoenzymatically synthesised enantiopure TAGs with a co-injection method. The method is applicable to many natural fats and oils of low unsaturation level assisting advanced investigation of lipid synthesis and metabolism. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of nine enantiopure structured triacylglycerols (TAGs) of the AAB type is described, all possessing the (S)-absolute configuration. Six of them possess one saturated and two identical unsaturated fatty acyl chains, whereas the remaining three possess two identical saturated fatty acids along with one unsaturated fatty acid. The former group was synthesized by a five-step chemoenzymatic route involving a highly regioselective immobilized Candida antarctica lipase, starting from enantiopure (R)-solketal. The second group was prepared by a fully chemical five-step approach based on the same chiral precursor. Such enantiopure TAGs are strongly required as standards for the enantiospecific analysis of intact TAGs in fats and oils. [Copyright &y& Elsevier]

• Twelve enantiopure asymmetric TAGs containing ALA, EPA and DHA were synthesized. • Unique TAGs offer reference material e.g. for bioavailability studies of n-3 PUFAs. • Chiral separation of structured TAG enantiomers was performed by chiral R-HPLC. • New information about stereospecific resolution of TAGs was received. • R-HPLC was applied to study enantiopurity (>98 %). The stereospecific structure of triacylglycerols (TAGs) affects the bioavailability of fatty acids. Lack of enantiopure reference compounds and effective enantiospecific methods have hindered the stereospecific analysis of individual TAGs. Twelve novel enantiostructured AAB-type TAGs were synthesized containing one of the three n-3 polyunsaturated fatty acid: α-linolenic acid (ALA), eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA) in sn -1 or sn -3 position. These compounds formed six enantiomer pairs, which were separated with recycling high-performance liquid chromatography using chiral columns and UV detection. The chromatographic retention behavior of the enantiomers and the stereospecific elution order were studied. The enantiomer with an n-3 PUFA in the sn -1 position eluted faster than the enantiomer with the n-3 PUFA in the sn -3 position, regardless of the carbon chain length and number of double bonds of the PUFA. TAG enantiomers containing DHA exhibited highly different retention on the chiral column and were separated after the first column, whereas recycling was needed to separate the enantiomer pairs containing ALA or EPA. The system using two identical columns and one mobile phase, without sample derivatization, proved to be very effective also for peak purity assessment, confirming the enantiopurity of the synthesized structured TAGs being higher than 98 % (96 % ee). [ABSTRACT FROM AUTHOR]

The synthesis of twelve enantiopure structured triacylglycerols (TAGs) of the ABC type possessing three different fatty acids is described by a six-step chemoenzymatic approach starting from (S)-solketal. Eight of the TAGs possess two different saturated fatty acyl groups located in the sn -1 and sn -2 positions with an unsaturated fatty acyl group in the remaining sn -3 position of the glycerol skeleton, whereas the remaining four possess two different saturated acyl groups in the terminal sn -1 and sn -3 positions with an unsaturated acyl group in the sn -2 position. The former group was synthesised by a six-step chemoenzymatic route involving a highly regioselective immobilised Candida antarctica lipase. The second group was prepared by a similar six-step approach, that required two separate lipase steps. Such enantiopure TAGs are strongly demanded as standards for enantiospecific analysis of intact TAGs in fats and oils. Image 1 • Twelve enantiostructured ABC type triacylglycerols (TAGs) were synthesised. • Unique TAGs as standards for chiral separation. • Facile methodology to synthesise both enantiomers of ABC type TAGs. • Highly regioselective lipase. [ABSTRACT FROM AUTHOR]