Long-chain polyunsaturated fatty acids (LCPUFAs) are essential for both fetal and placental development. We characterized the FA composition and gene expression levels of FA-metabolizing enzymes in rabbit placentas. Total FA compositions from term rabbit placentas (n = 7), livers, and plasma (both n = 4) were examined: among LCPUFAs with more than three double bonds, dihomo-γ-linolenic acid (DGLA) was the most abundant (11.4 ± 0.69 %, mean ± SE), while arachidonic acid was the second-most rich component (6.90 ± 0.56 %). DGLA was barely detectable (<1 %) in livers and plasma from term rabbits, which was significantly lower than in placentas (both p < 0.0001). Compared with the liver, transcript levels of the LCPUFA-metabolizing enzymes FADS2 and ELOVL5 were 7- and 4.5-fold higher in placentas (both p < 0.05), but levels of FADS1 and ELOVL2 were significantly lower (both p < 0.01). Our results suggest a placenta-specific enzyme expression pattern and LCPUFA profile in term rabbits, which may support a healthy pregnancy.

Very long-chain fatty acids (VLCFAs) are fatty acids with a carbon chain length greater than 18 carbons (>C18) and exhibit various functions, such as in skin barrier formation, liver homeostasis, myelin maintenance, spermatogenesis, retinal function, and anti-inflammation. VLCFAs are absorbed by dietary or elongated from endogenous hexadecanoyl acids (C16). Similar to long-chain fatty acid synthesis, VLCFAs elongation begins with acyl-CoA and malonyl-CoA as sources, and the length of the acyl chain is extended by two carbon units in each cycle. However, the VLCFAs elongation machinery is located in ER membrane and consists of four components, FA elongase (ELOVL), 3-ketoacyl-CoA reductase (KAR), 3-hydroxyacyl-CoA dehydratase (HACD), and trans-2-enoyl-CoA reductase (TECR), which is different with the long-chain fatty acid machinery fatty acid synthase (FAS) complex. Although the critical components in the elongation cycle are identified, the detailed catalytic and regulation mechanisms are still poorly understood. Here, we focused on the structural and biochemical analysis of TECR-associated VLCFA elongation reactions. Firstly, we identified a stable complex of human HACD2-TECR based on extensive in vitro characterizations. Combining computational modeling and biochemical analysis, we confirmed the critical interactions between TECR and HACD1/2. Then, we proposed the putative substrate binding sites and catalytic residues for TECR and HACD2. Besides, we revealed the structural similarities of HACD with ELOVLs and proposed the possible competition mechanism of TECR-associated complex formation.

Chicken is considered an ideal model species to study the synthesis of polyunsaturated fatty acids (PUFAs) due to its appropriate proportions of fatty acids and abundant content of PUFAs, suitable for human consumption. However, the molecular mechanisms regulating poultry PUFA synthesis remain unclear. Here, we systematically explored the transcriptional regulation activity of the gene family related to PUFA synthesis in chicken by carrying out the Dual-Luciferase Reporter Assay. We identified the core promoter regions of members of the chicken PUFA synthesis-related gene family, including ELOVL1, ELOVL2, ELOVL3, ELOVL4, ELOVL5, ELOVL6, ELOVL7, FADS1, FADS2, FADS6, SCD, and SCD5. Additionally, changes in relative fluorescence values of different truncated segments in the upstream regulatory region of these genes indicate the existence of regulatory regions. Furthermore, we predicted the transcription factors that bind to the identified core promoter regions of multiple genes, including Sp1, NF-1, C/EBPalpha, etc. These findings provide a basis for the molecular mechanisms regulating poultry PUFA synthesis and offer new scientific insight into the potential improvement of poultry meat quality in the future.

Despite their widespread associations with a wide variety of disease phenotypes, the genetics of red blood cell fatty acids remains understudied. We present one of the first genome-wide association studies of red blood cell fatty acid levels, using the Women\'s Health Initiative Memory study - a prospective cohort of N = 7,479 women aged 65-79. Approximately 9 million SNPs were measured directly or imputed and, in separate linear models adjusted for age and genetic principal components of ethnicity, SNPs were used to predict 28 different fatty acids. SNPs were considered genome-wide significant using a standard genome-wide significance level of p < 1 × 10-8. Twelve separate loci were identified, seven of which replicated results of a prior RBC-FA GWAS. Of the five novel loci, two have functional annotations directly related to fatty acids (ELOVL6 and ACSL6). While overall explained variation is low, the twelve loci identified provide strong evidence of direct relationships between these genes and fatty acid levels. Further studies are needed to establish and confirm the biological mechanisms by which these genes may directly contribute to fatty acid levels.

Mitochondria fuel most animal cells with ATP, ensuring proper energetic metabolism of organs. Early and extensive mitochondrial dysfunction often leads to severe disorders through multiorgan failure. Hacd2 gene encodes an enzyme involved in very long chain fatty acid (C ≥ 18) synthesis, yet its roles in vivo remain poorly understood. Since mitochondria function relies on specific properties of their membranes conferred by a particular phospholipid composition, we investigated if Hacd2 gene participates to mitochondrial integrity.
We generated two mouse models, the first one leading to a partial knockdown of Hacd2 expression and the second one, to a complete knockout of Hacd2 expression. We performed an in-depth analysis of the associated phenotypes, from whole organism to molecular scale.
Thanks to these models, we show that Hacd2 displays an early and broad expression, and that its deficiency in mice is lethal. Specifically, partial knockdown of Hacd2 expression leads to death within one to four weeks after birth, from a sudden growth arrest followed by cachexia and lethargy. The total knockout of Hacd2 is even more severe, characterized by embryonic lethality around E9.5 following developmental arrest and pronounced cardiovascular malformations. In-depth mechanistic analysis revealed that Hacd2 deficiency causes altered mitochondrial efficiency and ultrastructure, as well as accumulation of oxidized cardiolipin.
Altogether, these data indicate that the Hacd2 gene is essential for energetic metabolism during embryonic and postnatal development, acting through the control of proper mitochondrial organization and function.

The freshwater water flea Daphnia magna is a planktonic animal belonging to the Cladocera. To evaluate differences between two D. magna strains (KIT and NIES) in terms of life parameters and fatty acid profiles, we examined several endpoints. In the D. magna KIT strain, the numbers of total and cumulative offspring were lower at 23 °C and higher at 14 °C than in the D. magna NIES strain. However, at 14 °C, the D. magna KIT strain showed an increased lifespan. Although the n-3/n-6 polyunsaturated fatty acids (PUFA) ratio was always decreased at a low temperature, the PUFA ratio in the KIT strain had a higher value on day 3 than the NIES strain, which gave it higher adaptability to low temperature. In addition, we identified the elongation of very long chain fatty acids (elovl) and fatty acid desaturase (fad) genes, which are involved in fatty acid biosynthesis pathways, in the genomes of both D. magna KIT and NIES. The Elovl and Fad genes in both D. magna strains were highly conserved, including tandem duplicated Elovl 1/7 genes. This study provides new information about the molecular basis for the difference in temperature sensitivity between two strains of D. magna.

Depending on the presence and activities of the front-end fatty acyl desaturases and elongation of very long-chain fatty acid (Elovl) enzymes, animals have different capacities for long-chain (≥C20) polyunsaturated fatty acids (LC-PUFA) biosynthesis. Successful land colonisation in brachyuran crabs requires a shift towards terrestrial food chain with limited LC-PUFA availability. We cloned and functionally characterised two elovl genes from the purple land crab Gecarcoidea lalandii. The two Elovl contained all the necessary motifs of a typical polyunsaturated fatty acids (PUFA) Elovl and phylogenetically clustered in the Elovl1 and Elovl6 clades, respectively. The G. lalandii Elovl1 elongated saturated fatty acids, with low activities towards C20 and C22 PUFA substrates. Moreover, the G. lalandii Elovl6 was particularly active in the elongation of C18 PUFA, although it also recognised monounsaturated fatty acids as substrates for elongation. Collectively, the herein characterised G. lalandii elovl paralogues fulfil all the elongation steps involved in the LC-PUFA biosynthetic pathways. Tissue distribution of the G. lalandii elovl genes, along with the FA composition analyses, suggest the hepatopancreas and gill as key metabolic sites for fatty acid elongation. However, current data suggest that G. lalandii is unable to rely solely on biosynthesis to fulfil LC-PUFA requirements, since front-end desaturase appears to be absent in this species and other decapods.

The capacity for long-chain polyunsaturated fatty acid (LC-PUFA) biosynthesis activity in a species depends on the enzymatic activities of fatty acyl desaturase (Fads) and elongation of very long-chain fatty acid (Elovl). The miniaturized fish Paedocypris micromegethes is a developmentally truncated cyprinid living in highly acidic water conditions in tropical peat swamps. The capacity for LC-PUFA biosynthesis in this species, which has a reduced genome size, is unknown. A high-quality de novo transcriptome assembly enabled the identification of a putative Fads2 and four Elovl. The Fads2 was verified as a P. micromegethes Fads2 ortholog with in vitro Δ5 and Δ6 activities. The Elovl sequences were established as an Elovl5, Elovl2, and two Elovl4 paralogs, namely Elovl4a and Elovl4b. These Elovl enzymes, mainly Elovl5 and Elovl2, fulfill the necessary C18, C20, and C22 PUFA elongation steps for LC-PUFA biosynthesis. Collectively, these results validate the presence of a complete repertoire of LC-PUFA biosynthesis enzymes in a peat swamp miniatured freshwater fish.

n-3 and n-6 polyunsaturated fatty acids (PUFAs) are essential fatty acids that are provided by dietary intake. Growing evidence suggests that n-3 and n-6 PUFAs are paramount for brain functions. They constitute crucial elements of cellular membranes, especially in the brain. They are the precursors of several metabolites with different effects on inflammation and neuron outgrowth. Overall, long-chain PUFAs accumulate in the offspring brain during the embryonic and post-natal periods. In this review, we discuss how they accumulate in the developing brain, considering the maternal dietary supply, the polymorphisms of genes involved in their metabolism, and the differences linked to gender. We also report the mechanisms linking their bioavailability in the developing brain, their transfer from the mother to the embryo through the placenta, and their role in brain development. In addition, data on the potential role of altered bioavailability of long-chain n-3 PUFAs in the etiologies of neurodevelopmental diseases, such as autism, attention deficit and hyperactivity disorder, and schizophrenia, are reviewed.

The elongation of very long chain fatty acids (ELOVL) is a family of seven enzymes that have specific functions in the synthesis of fatty acids. Some have been shown to be related to insulin secretion (ELOVL2), and in the lipid profile (ELOVL6) and patients with various pathologies. The present work focused on the study of ELOVL polymorphs with clinical markers of non-communicable chronic diseases in the Mexican population. A sample of 1075 participants was obtained, who underwent clinical, biochemical, and nutritional evaluation, and a genetic evaluation of 91 genetic variants of ELOVL was considered (2-7). The results indicate a 33.16% prevalence of obesity by body mass index, 13.84% prevalence of insulin resistance by homeostatic model assessment (HOMA) index, 7.85% prevalence of high cholesterol, and 20.37% prevalence of hypercholesterolemia. The deprived alleles showed that there is no association between them and clinical disease risk markers, and the notable finding of the association studies is that the ELOVL2 variants are exclusive in men and ELVOL7 in women. There is also a strong association of ELOVL6 with various markers. The present study shows, for the first time, the association between the different ELOVLs and clinical markers of chronic non-communicable diseases.