Hepatocyte-Specific Fads1 Overexpression Attenuates Western Diet-Induced Metabolic Phenotypes in a Rat Model.

Fatty acid desaturase 1 (FADS1) is a rate-limiting enzyme in long-chain polyunsaturated fatty acid (LCPUFA) synthesis. Reduced activity of FADS1 was observed in metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this study was to determine whether adeno-associated virus serotype 8 (AAV8) mediated hepatocyte-specific overexpression of Fads1 (AAV8-Fads1) attenuates western diet-induced metabolic phenotypes in a rat model. Male weanling Sprague-Dawley rats were fed with a chow diet, or low-fat high-fructose (LFHFr) or high-fat high-fructose diet (HFHFr) ad libitum for 8 weeks. Metabolic phenotypes were evaluated at the endpoint. AAV8-Fads1 injection restored hepatic FADS1 protein levels in both LFHFr and HFHFr-fed rats. While AAV8-Fads1 injection led to improved glucose tolerance and insulin signaling in LFHFr-fed rats, it significantly reduced plasma triglyceride (by ~50%) and hepatic cholesterol levels (by ~25%) in HFHFr-fed rats. Hepatic lipidomics analysis showed that FADS1 activity was rescued by AAV8-FADS1 in HFHFr-fed rats, as shown by the restored arachidonic acid (AA)/dihomo-γ-linolenic acid (DGLA) ratio, and that was associated with reduced monounsaturated fatty acid (MUFA). Our data suggest that the beneficial role of AAV8-Fads1 is likely mediated by the inhibition of fatty acid re-esterification. FADS1 is a promising therapeutic target for MASLD in a diet-dependent manner.

Targeted Knockdown of Hepatic Δ-5 Fatty Acid Desaturase FADS1 Aggravates Atherosclerosis in ApoE-/- Mice.

BACKGROUND: The endogenous metabolism of polyunsaturated fatty acids is regulated by the fatty acid desaturase (FADS) gene cluster and is strongly associated with diseases such as atherosclerosis, dyslipidemia, and type 2 diabetes. However, the association between FADS and atherosclerosis remains a subject of debate. METHODS: In this study, we specifically investigated the physiological role of Δ-5 fatty acid desaturase (FADS1) in aortic and peripheral vessel (namely, the femoral artery) atherosclerosis by targeting the selective knockdown of hepatic Fads1 in apolipoprotein E-null (ApoE-⁣/-) mice with antisense oligonucleotides (ASOs). RESULTS: Knockdown of hepatic Fads1 in ApoE-⁣/- mice exacerbated aortic atherosclerosis and non-alcoholic fatty liver disease (NAFLD), resulting in weight loss. Upregulation of FADS1 mRNA expression in more severe atherosclerosis vascular tissues potentially caused the upregulation of angiopoietin-like 4 expression. CONCLUSIONS: Our study demonstrated that knockdown of hepatic Fads1 in ApoE-⁣/- mice aggravates spontaneous atherosclerosis and NAFLD but does not affect peripheral atherosclerosis (femoral artery) induced by vascular cuff combined with tandem stenosis.

A Metabolome-Wide Mendelian Randomization Study Identifies Dysregulated Arachidonic Acid Synthesis as a Potential Causal Risk Factor for Bipolar Disorder.

BACKGROUND: Bipolar disorder (BPD) is a debilitating mood disorder with an unclear etiology. A better understanding of the underlying pathophysiological mechanisms will help to identify novel targets for improved treatment options and prevention strategies. In this metabolome-wide Mendelian randomization study, we screened for metabolites that may have a causal role in BPD. METHODS: We tested a total of 913 circulating metabolite exposures assessed in 14,296 Europeans using a mass spectrometry-based platform. For the BPD outcome, we used summary data from the largest and most recent genome-wide association study reported to date, including 41,917 BPD cases. RESULTS: We identified 33 metabolites associated with BPD (padjusted < 5.48 × 10-5). Most of them were lipids, including arachidonic acid (ß = -0.154, SE = 0.023, p = 3.30 × 10-11), a polyunsaturated omega-6 fatty acid, along with several complex lipids containing either an arachidonic or a linoleic fatty acid side chain. These associations did not extend to other closely related psychiatric disorders like schizophrenia or depression, although they may be involved in the regulation of lithium response. These lipid associations were driven by genetic variants within the FADS1/2/3 gene cluster, which is a robust BPD risk locus encoding a family of fatty acid desaturase enzymes that are responsible for catalyzing the conversion of linoleic acid into arachidonic acid. Statistical colocalization analyses indicated that 27 of the 33 metabolites shared the same genetic etiology with BPD at the FADS1/2/3 cluster, demonstrating that our findings are not confounded by linkage disequilibrium. CONCLUSIONS: Overall, our findings support the notion that arachidonic acid and other polyunsaturated fatty acids may represent potential targets for BPD.

Expression of genes and localization of enzymes involved in polyunsaturated fatty acid synthesis in rabbit testis and epididymis.

The metabolism of polyunsaturated fatty acids (PUFAs) plays an important role in male reproduction. Linoleic and alpha-linolenic acids need to be provided in the diet and they are converted into long chain polyunsaturated fatty acids by steps of elongation and desaturation, exerted by elongases 2 (ELOVL2) and 5 (ELOVL5) and Δ5- (FADS1) and Δ6-desaturase (FADS2). This study aims to assess the gene expression and localization of enzymes involved in the synthesis of n-3 and n-6 long-chain PUFAs in control rabbits and those fed diets containing 10% extruded flaxseed. Enzyme and PUFA localization were assessed in the testes and epididymis by immunofluorescence. Testes showed high gene expression of FADS2, ELOVL2 and ELOVL5 and low expression of FADS1. Intermediate metabolites, enzymes and final products were differently found in Leydig, Sertoli and germinal cells. FADS2 was localized in interstitial cells and elongated spermatids; ELOVL5 in meiotic cells; FADS1 was evident in interstitial tissue, Sertoli cells and elongated spermatids; ELOVL2 in interstitial cells. Epididymal vesicles were positive for FADS1, ELOVL2 and ELOVL5 as well as docosahexaenoic, eicosapentaenoic, and arachidonic acids. This knowledge of fatty acids (FA) metabolism in spermatogenesis and the influence of diet on FA profile could help identify causes of male infertility, suggesting new personalized therapy.

High-dose ferric citrate supplementation attenuates omega-3 polyunsaturated fatty acid biosynthesis via downregulating delta 5 and 6 desaturases in rats with high-fat diet-induced obesity.

Obesity is associated with an increased risk of an iron deficiency; however, a synergistic relationship between iron and lipid homeostasis was also observed. The aim of this study was to investigate the effects of pharmacological doses of iron supplementation on omega 3 (n-3) and omega 6 (n-6) polyunsaturated fatty acids (PUFAs). Sprague-Dawley (SD) rats were fed a normal diet or a 50% high-fat diet (HFD) without or with pharmacological doses of ferric citrate (0.25, 1, or 2 g ferric iron per kg diet) for 12 weeks, and erythrocyte profiles of n-3 and n-6 PUFAs were quantitated. Ferric citrate supplementation showed dose-related effects on liver inflammation, liver iron accumulation, and increasing circulating levels of iron, erythrocyte degradation biomarkers LVV-hemorphin-7, malondialdehyde (MDA), and insulin. Obese rats supplemented with 2 g ferric iron per kg diet also had decreased levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and total n-3 PUFAs compared to rats fed a normal diet or HFD alone. A western blotting analysis revealed that iron-mediated downregulation of n-3 PUFA-converting enzymes (Δ5 and Δ6 desaturases) only occurred at high dosages (≥1 g ferric iron per kg diet). A Spearman correlation analysis showed that total liver iron and serum LVV-hemorphin-7 and MDA were negatively correlated with n-3 PUFAs and their converting enzymes (Δ5 and Δ6 desaturases) (all p < 0.05). In conclusion, obese rats that received high-dose ferric citrate supplementation (>1 g of ferric iron per kg diet) exhibited decreased n-3 PUFA levels via downregulation of expressions of Δ5 and Δ6 desaturase enzymes.

The aromatase inhibitor letrozole restores FADS2 function in ER+ MCF7 human breast cancer cells.

PURPOSE: Plasticity in fatty acid metabolism is increasingly recognized as a major feature influencing cancer progression and efficacy of treatments. Estrogen receptor positive MCF7 human breast cancer cells have long been known to have no FADS2-mediated Δ6-desaturase activity. Our objective was to examine the effect of estrogen and the "antiestrogen" aromatase inhibitor letrozole, on Δ5- and Δ6-desaturase synthesized fatty acids in vitro. METHODS: Eicosa-11,14-dienoic acid (20:2n-6), a known substrate for both FADS1 and FADS2, was used as a sentinel of relative FADS2 and FADS1 activity. MCF7 cells and four additional estrogen responsive wild type cell lines (HepG2, SK-N-SH, Y79 and Caco2) were studied. FAME were quantified by GC-FID and structures identified by GCCACI-MS/MS. RESULTS: In all five cell lines, estrogen caused a dose dependent decrease in sciadonic acid (5,11,14-20:3, ScA) via apparent inhibition of FADS1 activity, and had no effect on FADS2 catalyzed synthesis of dihomo-gamma linolenic acid (8,11,14-20:3; DGLA). In MCF7 cells, letrozole caused a dose dependent increase in FADS2-catalyzed DGLA synthesis, which plateaued in SK-N-SH cells. CONCLUSION: Letrozole restores Δ6-desaturase mediated synthesis of the anti-inflammatory PGE1-precursor DGLA in vitro and is the first endocrine-active agent to have opposing effects on FADS1 and FADS2 catalyzed activities.

Direct and pleiotropic effects of the Masou Salmon Delta-5 Desaturase transgene in F1 channel catfish (Ictalurus punctatus).

Channel catfish (Ictalurus punctatus) is the primary culture species in the US along with its hybrid made with male blue catfish, I. furcatus. In an effort to improve the nutritional value of channel catfish, the masou salmon Δ5-desaturase like gene (D5D) driven by the common carp beta-actin promoter (ßactin) was inserted into channel catfish. The objectives of this study were to determine the effectiveness of ßactin-D5D for improving n-3 fatty acid production in F1 transgenic channel catfish, as well as examine pleiotropic effects on growth, proximate analysis, disease resistance, and other performance traits. Transgenic F1 channel catfish showed a 33% increase in the relative proportion of n-3 fatty acids coupled with a 15% decrease in n-6 fatty acids and a 17% decrease in n-9 fatty acids when compared to non-transgenic full-siblings (P < 0.01, P < 0.01, P < 0.01). However, while the relative proportion of n-3 fatty acids was achieved, the total amount of fatty acids in the transgenic fish decreased resulting in a reduction of all fatty acids. Insertion of the ßactin-D5D transgene into channel catfish also had large effects on the body composition, and growth of channel catfish. Transgenic channel catfish grew faster, were more disease resistant, had higher protein and moisture percentage, but lower fat percentage than full-sib controls. There were sex effects as performance changes were more dramatic and significant in males. The ßactin-D5D transgenic channel catfish were also more uniform in their fatty acid composition, growth and other traits.