Desaturase and elongase-limiting endogenous long-chain polyunsaturated fatty acid biosynthesis

Zhang, Ji Yao; Kothapalli, Kumar S.D.; Brenna, J. Thomas

doi:10.1097/mco.0000000000000254

Cited by 159 publications

(166 citation statements)

References 59 publications

(96 reference statements)

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“…The two major factors that determine n-3 and n-6 PUFA levels – dietary PUFA intake and variants in FA desaturase and elongase genes - were not explored here, in part because they were beyond the scope of this study, but also because of their own inherent limitations. Estimated PUFA intakes derived from food records are inferior to circulating PUFA levels as indicators of PUFA exposure 64, 65 , and the effects of genetic variants on PUFA levels, while substantial for ARA 66 , are minimal to non-existent for EPA and DHA 67 . Finally, the inability to rule out the possibility of residual or unmeasured confounding also precludes inferences about causality 68 .…”

Section: Discussionmentioning

confidence: 98%

Red blood cell polyunsaturated fatty acids and mortality in the Women's Health Initiative Memory Study

Harris

Luo

Pottala

et al. 2017

Journal of Clinical Lipidology

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Background The prognostic value of circulating polyunsaturated fatty acid (PUFA) levels is 4unclear. Objectives To determine the associations between red blood cell (RBC) PUFA levels and risk for death. Methods This prospective cohort study included 6501 women aged 65–80 who participated in the Women’s Health Initiative Memory Study (enrolment began 1996). RBC PUFA levels were measured at baseline and expressed as a percent of total RBC PUFAs. PUFAs of primary interest were the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their sum (the Omega-3 Index). PUFA of secondary interest included the two major n-6 PUFAs, linoleic (LA) and arachidonic (ARA), and the PUFA Factor score (a calculated variable including 6 PUFAs that accounts for their inter-correlations). The primary outcome was total mortality through August 2014. Results After a median of 14.9 years of follow-up, 1851 (28.5%) women had died. RBC levels of EPA and DHA were higher in the survivors (p<0.002 for each). In the fully adjusted models, the hazard ratios (99% confidence intervals) for mortality associated with a 1-SD PUFA increase for total mortality were 0.92 (0.85, 0.98) for the Omega-3 Index, 0.89 (0.82, 0.96) for EPA, 0.93 (0.87, 1.0) for DHA, and 0.76 (0.64, 0.90) for the PUFA Factor score. There were no significant associations of alpha-linolenic acid or ARA or LA with total mortality. Conclusions Higher RBC levels of marine n-3 PUFAs were associated with reduced risk for all-cause mortality. These findings support the beneficial relationship between the Omega-3 Index and health outcomes. ClinicalTrials.gov Identifier NCT00000611 (WHIMS).

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Section: Discussionmentioning

confidence: 98%

Red blood cell polyunsaturated fatty acids and mortality in the Women's Health Initiative Memory Study

Harris

Luo

Pottala

et al. 2017

Journal of Clinical Lipidology

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“…Note that the presence of the ELOVL4 protein in the tarsal plates has been verified using immunohistochemical staining with ELOVL4-specific antibodies, and so was the expression of ELOVL3. Detailed descriptions of putative mechanisms of the FA elongation cycle can be found in several reviews for example (Guillou et al, 2010; Jakobsson et al, 2006; Kihara, 2012; Zhang et al, 2016). …”

Section: A Concept Of Meibogenesismentioning

confidence: 99%

“…Conversely, FADS2/Fads2 – a gene that encodes a fatty acid desaturase-2 (FADS2) – is only modestly expressed in TP of humans and mice [(Butovich et al, 2016)]. FADS2 [(Guillou et al, 2010; Nakamura and Nara, 2004; Tosi et al, 2014)] catalyzes Δ4- and Δ6-desaturation of C 20 -C 24 polyunsaturated FA, with four or more double bonds making, for example, docosahexaenoic acid in humans and rodents (Zhang et al, 2016). Again, its modest expression level (45% or so) in tarsal plates is consistent with a low abundance of its expected products – PUFA with three or more double bonds.…”

Section: A Concept Of Meibogenesismentioning

confidence: 99%

Meibomian glands, meibum, and meibogenesis

Butovich

2017

Experimental Eye Research

106

118

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Meibum is a lipid-rich secretion that is produced by fully differentiated meibocytes in the holocrine Meibomian glands (MG) of humans and most mammals. The secretion is a part of a defense mechanism that protects the ocular surface from hazardous environmental factors, and from desiccation. Meibomian lipids that have been identified in meibum are very diverse and unique in nature. The lipid composition of meibum is different from virtually any other lipid pool found in the human body. In fact, meibum is quite different from sebum, which is the closest secretion that is produced by anatomically, physiologically, and biochemically related sebaceous glands. However, meibum of mice have been shown to closely resemble that of humans, implying similar biosynthetic mechanisms in MG of both species. By analyzing available genomic, immunohistochemical, and lipidomic data, we have envisioned a unifying network of enzymatic reactions that are responsible for biosynthesis of meibum, which we call meibogenesis. Our current theory is based on an assumption that most of the biosynthetic reactions of meibogenesis are catalyzed by known enzymes. However, the main features that make meibum unique – the ratio of identified classes of lipids, the extreme length of its components, extensive ω-hydroxylation of fatty acids and alcohols, iso- and anteiso-branching of meibomian lipids (e.g. waxes), and the presence of rather unique complex lipids with several ester bonds – make it possible that either the activity of known enzymes is altered in MG, or some unknown enzymes contribute to the processes of meibogenesis, or both. Studies are in progress to elucidate meibogenesis on molecular level.

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“…Long chain PUFA can be endogenously derived from (LA) or (ALA) by a consecutive series of desaturations (involving the Delta-6 desaturase encoded by the FADS2 (fatty acid desaturase 2) gene and the Delta-5 desaturase, encoded by the FADS1 (fatty acid desaturase 1) gene and elongation steps, as well as oxidation. Among the seven elongases, ELOVL2 (elongation of very long chain fatty acids 2) and ELOVL5 elongation of very long chain fatty acids 5) are PUFA-specific [4]. Docosahexaenoic acid (DHA) is a long-chain, highly unsaturated omega-3 fatty acid, synthesized from the ALA in this process.…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Association Study for Serum Omega-3 and Omega-6 Polyunsaturated Fatty Acids: Exploratory Analysis of the Sex-Specific Effects and Dietary Modulation in Mediterranean Subjects with Metabolic Syndrome

et al. 2020

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Many early studies presented beneficial effects of polyunsaturated fatty acids (PUFA) on cardiovascular risk factors and disease. However, results from recent meta-analyses indicate that this effect would be very low or nil. One of the factors that may contribute to the inconsistency of the results is that, in most studies, genetic factors have not been taken into consideration. It is known that fatty acid desaturase (FADS) gene cluster in chromosome 11 is a very important determinant of plasma PUFA, and that the prevalence of the single nucleotide polymorphisms (SNPs) varies greatly between populations and may constitute a bias in meta-analyses. Previous genome-wide association studies (GWAS) have been carried out in other populations and none of them have investigated sex and Mediterranean dietary pattern interactions at the genome-wide level. Our aims were to undertake a GWAS to discover the genes most associated with serum PUFA concentrations (omega-3, omega-6, and some fatty acids) in a scarcely studied Mediterranean population with metabolic syndrome, and to explore sex and adherence to Mediterranean diet (MedDiet) interactions at the genome-wide level. Serum PUFA were determined by NMR spectroscopy. We found strong robust associations between various SNPs in the FADS cluster and omega-3 concentrations (top-ranked in the adjusted model: FADS1-rs174547, p = 3.34 × 10−14; FADS1-rs174550, p = 5.35 × 10−14; FADS2-rs1535, p = 5.85 × 10−14; FADS1-rs174546, p = 6.72 × 10−14; FADS2-rs174546, p = 9.75 × 10−14; FADS2-rs174576, p = 1.17 × 10−13; FADS2-rs174577, p = 1.12 × 10−12, among others). We also detected a genome-wide significant association with other genes in chromosome 11: MYRF (myelin regulatory factor)-rs174535, p = 1.49 × 10−12; TMEM258 (transmembrane protein 258)-rs102275, p = 2.43 × 10−12; FEN1 (flap structure-specific endonuclease 1)-rs174538, p = 1.96 × 10−11). Similar genome-wide statistically significant results were found for docosahexaenoic fatty acid (DHA). However, no such associations were detected for omega-6 PUFAs or linoleic acid (LA). For total PUFA, we observed a consistent gene*sex interaction with the DNTTIP2 (deoxynucleotidyl transferase terminal interacting protein 2)-rs3747965 p = 1.36 × 10−8. For adherence to MedDiet, we obtained a relevant interaction with the ME1 (malic enzyme 1) gene (a gene strongly regulated by fat) in determining serum omega-3. The top-ranked SNP for this interaction was ME1-rs3798890 (p = 2.15 × 10−7). In the regional-wide association study, specifically focused on the FADS1/FASD2/FADS3 and ELOVL (fatty acid elongase) 2/ELOVL 5 regions, we detected several statistically significant associations at p < 0.05. In conclusion, our results confirm a robust role of the FADS cluster on serum PUFA in this population, but the associations vary depending on the PUFA. Moreover, the detection of some sex and diet interactions underlines the need for these associations/interactions to be studied in all specific populations so as to better understand the complex metabolism of PUFA.

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Desaturase and elongase-limiting endogenous long-chain polyunsaturated fatty acid biosynthesis

Cited by 159 publications

References 59 publications

Red blood cell polyunsaturated fatty acids and mortality in the Women's Health Initiative Memory Study

Red blood cell polyunsaturated fatty acids and mortality in the Women's Health Initiative Memory Study

Meibomian glands, meibum, and meibogenesis

Genome-Wide Association Study for Serum Omega-3 and Omega-6 Polyunsaturated Fatty Acids: Exploratory Analysis of the Sex-Specific Effects and Dietary Modulation in Mediterranean Subjects with Metabolic Syndrome

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