Functional Impact of the FADS1 rs174546 Single Nucleotide Polymorphism on Serum Lipid Levels: Insights from Molecular Mechanisms and Therapeutic Perspectives in Korean Population.

SCOPE: Single nucleotide polymorphisms (SNP) in the fatty acid desaturase 1 (FADS1) gene is suggested as risk factor of metabolic diseases in genome-wide association studies (GWAS). This study hypothesized that FADS1_rs174546T associates with serum triglycerides (TG) in Korean Genome and Epidemiology Study (KoGES). In addition, functional study of SNP genotypes in cultured cells is performed. METHODS AND RESULTS: FADS1_rs174546T is associated with high level of serum TG (effect size of variant: 6.48 ± 1.84 mg dL-1) in Korean individuals (normotriglyceridemia, n = 5128; hypertriglyceridemia, n = 3714). Functional study in cells with FADS1_rs174546T, shows reduced transcriptional activity, when compared with rs174546C. MiR-6728-3p, which is predicted to bind with rs174546T, decreases transcriptional activity of rs174546T but not in rs174546C, and it is reversed by miR-6728-3p inhibitor. Formononetin is selected as binding molecule to 3'-UTR of FADS1 and increases luciferase activity in both rs174546 (C/T). Moreover, formononetin compensates for the reduced luciferase activity by rs174546T and miR-6728-3p. Formononetin also increases endogenous FADS1 expression and long-chain polyunsaturated fatty acid (LC-PUFA) ratio. CONCLUSION: FADS1_rs174546T is a crucial risk factor for hypertriglyceridemia in the Koreans potentially through the interaction with miR-6728-3p. Formononetin can be a potent dietary intervention to prevent and improve hypertriglyceridemia in both rs174546 (C/T) populations.

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.

Association of Fatty Acid Desaturase 1 rs174547 Polymorphism with the Composition of Long-Chain Polyunsaturated Fatty Acids in Serum Glycerophospholipids during Pregnancy.

The increase in fetal requirements of long-chain polyunsaturated fatty acids (LCPUFAs) during pregnancy alters maternal fatty acid metabolism, and therefore, fatty acid desaturase (FADS) gene polymorphisms may change blood fatty acid composition or concentration differently during pregnancy. We investigated the relationship between a FADS1 single-nucleotide polymorphism (SNP) and maternal serum LCPUFA levels in Japanese pregnant women during the first and third trimesters and at delivery. Two hundred and fifty-three pregnant women were included, and fatty acid compositions of glycerophospholipids in serum (weight %) and the FADS1 SNP rs174547 (T/C) were analyzed. LCPUFAs, including arachidonic acid (ARA) and docosahexaenoic acid (DHA), significantly decreased from the first to the third trimester of pregnancy. Furthermore, DHA significantly decreased from the third trimester of pregnancy to delivery. At all gestational stages, linoleic acid (LA) and α-linolenic acid were significantly higher with the number of minor FADS1 SNP alleles, whereas γ-linolenic acid and ARA and the ARA/LA ratio were significantly lower. DHA was significantly lower with the number of minor FADS1 SNP alleles only in the third trimester and at delivery, suggesting that genotype effects become more obvious as pregnancy progresses.

Cadmium perturbed lipid profile and induced liver dysfunction in mice through phosphatidylcholine remodeling and promoting arachidonic acid synthesis and metabolism.

Cadmium ion (Cd2+) exposure has been reported to associate with the prevalence of dyslipidemia, and contribute to the initiation and progression of nonalcoholic fatty liver disease (NAFLD). However, Cd2+ exposure perturbed specific metabolic pathways and underlying mechanisms are still unclear. In the present study, through lipidomics analyses of differential metabolites in serum between the Cd2+-exposed mice and the control group, 179 differential metabolites were identified, among which phosphatidylcholines (PCs) accounted for 49 % metabolites. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment assay indicates that PCs participate in the metabolic pathways, including the Arachidonic Acid (AA) metabolism, which also could be potential NAFLD biomarkers. Moreover, in vivo and in vitro results suggested that Cd2+ exposure induced PC synthesis and remodeling, and increased AA level by promoting fatty acid desaturase 1 (FADS1) to catalyze synthesis process instead of cytosolic phospholipase A2 (cPLA2) mediated release pathway. Inhibition of FADS1 by T3364366 could reverse Cd-induced AA, prostaglandin E2 (PGE2) and triglyceride (TAG) levels, and it also reduce cisplatin resistance in HepG2 cells. This study provides new evidence of Cd2+-induced dyslipidemia and reveals underlying molecular mechanism involved in liver dysfunction of Cd2+ exposure.

Diet Regulation of Long-Chain PUFA Synthesis: Role of Macronutrients, Micronutrients, and Polyphenols on Δ-5/Δ-6 Desaturases and Elongases 2/5.

Deficiencies in the n-3 (ω-3) long-chain PUFAs (LC-PUFAs) EPA and DHA are associated with increased risk for the development of numerous diseases. Although n-3 LC-PUFAs can be obtained by consuming marine products, they are also synthesized endogenously through a biochemical pathway regulated by the Δ-5/Δ-6 desaturase and elongase 2/5 enzymes. This narrative review collates evidence from the past 40 y demonstrating that mRNA expression and activity of desaturase and elongase enzymes are influenced by numerous dietary components, including macronutrients, micronutrients, and polyphenols. Specifically, we highlight that both the quantity and the composition of dietary fats, carbohydrates, and proteins can differentially regulate desaturase pathway activity. Furthermore, desaturase and elongase mRNA levels and enzyme activities are also influenced by micronutrients (folate, vitamin B-12, vitamin A), trace minerals (iron, zinc), and polyphenols (resveratrol, isoflavones). Understanding how these various dietary components influence LC-PUFA synthesis will help further advance our understanding of how dietary patterns, ranging from caloric excesses to micronutrient deficiencies, influence disease risks.

The Relationship Between Cognitive Status and Known Single Nucleotide Polymorphisms in Age-Related Macular Degeneration.

Recent literature has reported a higher occurrence of cognitive impairment among individuals with Age-related Macular Degeneration (AMD) compared to older adults with normal vision. This pilot study explored potential links between single nucleotide polymorphisms (SNPs) in AMD and cognitive status. Individuals with AMD (N = 21) and controls (N = 18) were genotyped for the SNPs CFHY402H, ARMS2A69S and FADS1 rs174547. Cognitive status was evaluated using the Montreal Cognitive Assessment. The two groups differed significantly on which subscales were most difficult. The control group had difficulty with delayed recall while those with AMD had difficulty on delayed recall in addition to abstraction and orientation. Homozygous carriers of the FADS1 rs174547 SNP had significantly lower scores than heterozygotes or non-carriers on the MoCA. The results suggest that the FADS1 SNP may play a role in visual impairment/cognitive impairment comorbidity as reflected in the poorer cognitive scores among homozygotes with AMD compared to those carrying only one, or no copies of the SNP.

Genetic variants in FADS1 and ELOVL2 increase level of arachidonic acid and the risk of Alzheimer's disease in the Tunisian population.

Polyunsaturated fatty acids (PUFAs) are closely related to various physiological conditions. In several age-related diseases including Alzheimer's disease (AD) altered PUFAs metabolism has been reported. However, the mechanism behind PUFAs impairment and AD developpement remains unclear. In humans, PUFAs biosynthesis requires delta-5 desaturase (D5D), delta-6 desaturase (D6D) and elongase 2 activities; which are encoded by fatty acid desaturase 1 (FADS1), fatty acid desaturase 2 (FADS2), and elongation of very-long-chain fatty acids-like 2 (ELOVL2) genes, respectively. In the present work, we aim to assess whether genetic variants in FADS1, FADS2 and ELOVL2 genes influence plasma and erythrocyte PUFA composition and AD risk. A case-control study was carried out in 113 AD patients and 161 healthy controls.Rs174556, rs174617, and rs3756963 of FADS1, FADS2, and ELOVL2 genes, respectively were genotyped using PCR-RFLP. PUFA levels were quantified using Gas Chromatography. Genotype distributions of rs174556 (FADS1) and rs3756963 (ELOVL2) were different between case and control groups. The genotype TT of rs174556 and rs3756963 single nucleotide polymorphism (SNP) increases significantly the risk of AD in our population. PUFA analysis showed higher plasma and erythrocyte arachidonic acid (AA) level in patients with AD, whereas only plasma docosahexaenoic acid (DHA) was significantly decreased in AD patients. The indexes AA/Dihomo-gamma-linolenic acid (DGLA) and C24:4n-6/Adrenic acid (AdA) were both higher in the AD group. Interestingly, patients with TT genotype of rs174556 presented higher AA level and AA/DGLA index in both plasma and erythrocyte. In addition, higher AA and AA/DGLA index were observed in erythrocyte of TT genotype ofrs3756963 carrier's patients. Along with, positive correlation between AA/DGLA index, age or Gamma-linolenic acid (GLA)/ Linoleic acid (LA) index was seen in erythrocyte and /or plasma of AD patients. After adjustment for confounding factors, the genotype TT of rs174556, erythrocyte AA and AA/DGLA index were found to be predictive risk factors for AD while plasma DHA was found associated with lower AD risk. Both rs174556 and rs3756963 influence AD risk in the Tunisian population and they are likely associated with high AA level. The combination of the two variants increases further the susceptibility to AD. We suggest that FADS1 and ELOVL2 variants could likely regulate the efficiency of AA biosynthesis which could be at the origin of inflammatory derivate.

Suppression of FADS1 induces ROS generation, cell cycle arrest, and apoptosis in melanocytes: implications for vitiligo.

Vitiligo is a potentially serious condition characterized by loss of melanin and death of melanocytes. To identify potential therapeutic targets for vitiligo, we conducted a microarray analysis of three human vitiligo specimens and paired adjacent normal tissues. Because we found that the fatty acid desaturase 1 (FADS1) gene was downregulated in vitiligo specimens, we carried out experiments to assess its role in melanocyte replication and survival. RT-qPCR was used to verify that FADS1 expression was lower in vitiligo-affected tissues and vitiligo melanocyte PIG3V cells than in matched controls or normal human epidermal PIG1 melanocytes. In addition, CCK-8, immunofluorescence, western blot and flow cytometry assay were used to detect the proliferation and apoptosis in PIG1 cells respectively. Overexpression of FADS1 promoted proliferation of PIG3V melanocytes, while FADS1 silencing inhibited proliferation and induced cell death in PIG1 melanocytes. Increased ROS generation; induction of mitochondrial-mediated apoptosis via upregulation of Bax and active caspases 3 and 9 and downregulation of Bcl-2; and cell cycle arrest via downregulation of c-Myc and Cyclin D1 and upregulation of p21 were all enhanced after FADS1 silencing in PIG1 melanocytes. These findings implicate FADS1 downregulation in the pathogenesis of vitiligo and may open new avenues for its treatment.

Interaction of Dietary Linoleic Acid and α-Linolenic Acids with rs174547 in FADS1 Gene on Metabolic Syndrome Components among Vegetarians.

Fatty acid desaturase 1 (FADS1) gene controls the fatty acid metabolism pathway in the human body. The lower intake of α-linolenic acid (ALA) than linoleic acid (LA) among vegetarians may disrupt the fatty acid metabolism and limit the conversion of ALA to anti-inflammatory products such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This cross-sectional study aimed to determine the interaction of rs174547 in FADS1 gene with LA and ALA on metabolic syndrome (MetS) components. A total of 200 Chinese and Indian vegetarians in Kuala Lumpur and Selangor, Malaysia participated in the present study. The data on socio-demographic characteristics, vegetarianism practices, dietary practices, anthropometric measurements, blood pressure (BP), and overnight venous fasting blood samples were collected from the vegetarians. The rs174547 in FADS1 gene was significantly associated with MetS and its components such as waist circumference (WC) and fasting blood glucose (FBG). Multiple logistic regression analyses revealed that vegetarians with TT genotype of rs174547 in FADS1 gene had higher odds for MetS, larger WC, higher BP, and a lower level of HDL-c. Two-way ANOVA analysis showed that LA interacts with rs174547 in FADS1 gene to affect HDL-c (p < 0.05) among vegetarians. The present findings suggest the need to develop dietary guidelines for vegetarians in Malaysia. Prospective studies are also needed to affirm the interaction between LA and rs174547 in FADS1 gene on HDL-c among Malaysian vegetarians.

Comparing the serum TAG response to high-dose supplementation of either DHA or EPA among individuals with increased cardiovascular risk: the ComparED study.

Studies have shown that the reduction in serum TAG concentrations with long-chain n-3 fatty acid supplementation is highly variable among individuals. The objectives of the present study were to compare the proportions of individuals whose TAG concentrations lowered after high-dose DHA and EPA, and to identify the predictors of response to both modalities. In a double-blind, controlled, crossover study, 154 men and women were randomised to three supplemented phases of 10 weeks each: (1) 2·7 g/d of DHA, (2) 2·7 g/d of EPA and (3) 3 g/d of maize oil, separated by 9-week washouts. As secondary analyses, the mean intra-individual variation in TAG was calculated using the standard deviation from the mean of four off-treatment samples. The response remained within the intra-individual variation (±0·25 mmol/l) in 47 and 57 % of participants after DHA and EPA, respectively. Although there was a greater proportion of participants with a reduction >0·25 mmol/l after DHA than after EPA (45 υ. 32 %; P 0·25 mmol/l after both DHA and EPA had higher non-HDL-cholesterol, TAG and insulin concentrations compared with other responders at baseline (all P < 0·05). In conclusion, supplementation with 2·7 g/d DHA or EPA had no meaningful effect on TAG concentrations in a large proportion of individuals with normal mean TAG concentrations at baseline. Although DHA lowered TAG in a greater proportion of individuals compared with EPA, the magnitude of TAG lowering among them was similar.

Evaluating Changes in Omega-3 Fatty Acid Intake after Receiving Personal FADS1 Genetic Information: A Randomized Nutrigenetic Intervention.

Nutrigenetics research is anticipated to lay the foundation for personalized dietary recommendations; however, it remains unclear if providing individuals with their personal genetic information changes dietary behaviors. Our objective was to evaluate if providing information for a common variant in the fatty acid desaturase 1 (FADS1) gene changed omega-3 fatty acid (FA) intake and blood levels in young female adults (18-25 years). Participants were randomized into Genetic (intervention) and Non-Genetic (control) groups, with measurements taken at Baseline and Final (12 weeks). Dietary intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) was assessed using an omega-3 food frequency questionnaire. Red blood cell (RBC) FA content was quantified by gas chromatography. Implications of participation in a nutrigenetics study and awareness of omega-3 FAs were assessed with online questionnaires. Upon completion of the study, EPA and DHA intake increased significantly (p = 1.0 × 10-4) in all participants. This change was reflected by small increases in RBC %EPA. Participants in the Genetic group showed increased awareness of omega-3 terminology by the end of the study, reported that the dietary recommendations were more useful, and rated cost as a barrier to omega-3 consumption less often than those in the Non-Genetic group. Providing participants FADS1 genetic information did not appear to influence omega-3 intake during the 12 weeks, but did change perceptions and behaviors related to omega-3 FAs in this timeframe.

Novel polymorphism in FADS1 gene and fish consumption on risk of oral cancer: A case-control study in southeast China.

The aim of this study was to investigate the independent and combined effects of fatty acid desaturase 1 (FADS1) gene polymorphism and fish consumption on oral cancer. A hospital-based case-control study was performed including 305 oral cancer patients and 579 cancer-free controls. The genotypes were determined by TaqMan genotyping assay. Non-conditional logistic regression model was used to assess the effects of FADS1 rs174549 polymorphism and fish intake. Subjects carrying A allele of rs174549 significantly reduced the risk of oral cancer (AA VS GG, OR: 0.65, 95% CI: 0.42-0.99; AA VS AG+GG, OR: 0.67, 95% CI: 0.46-0.98). Moreover, the statistically significant reverse associations were especially evident in men, smokers, alcohol drinkers and those age ≤ 60 years. Additionally, fish intake ≥7 times/week showed a 73% reduction in risk for oral cancer compared to those who ate fish less than 2 times/week (OR: 0.27, 95% CI: 0.18-0.42). Furthermore, a significant gene-diet multiplicative interaction was observed between FADS1 rs174549 polymorphism and fish intake for oral cancer (P=0.028). This preliminary study suggests that FADS1 rs174549 polymorphism and fish consumption may be protective factors for oral cancer, with a gene-diet multiplicative interaction. Functional studies with larger samples are required to confirm our findings.

Single nucleotide polymorphisms of the DGKB and VCAM1 genes are associated with granulocyte colony stimulating factor-mediated peripheral blood stem cell mobilization.

We previously reported the association between LDL cholesterol level (LDL-C) and granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood (PB) hematopoietic stem cells (HSC). In this study, we investigated the association between gene single nucleotide polymorphisms (SNPs) involved in hematopoiesis and lipid level and PBHSC mobilization. In 46 patients who underwent peripheral blood stem cell harvest (PBSCH), we measured CD34-positive cells in PB and PBSCH, and the patients were classified into good, intermediate, or poor mobilizer groups based on the CD34-positive cell counts. And SNPs of the OR4C12, ENO1, RERE, DGKB, DSC3, VCAM1, CD44, and FADS1 genes were investigated. The frequency of the TT type of the DGKB gene was higher in the poor mobilizer group compared to other groups (p<0.05), whereas that of the CC type of the VCAM1 gene was high in the good mobilizer group (p<0.05). Association with the efficiency of HSC mobilization to PB were found in the SNPs of the DGKB gene involved in cell transport and SDF-1-induced migration ability and of the VCAM1 gene which is essential for HSC homing, suggesting that SNPs involved in cell migration ability might be partly involved in HSC mobilization to PB.

[Fatty acid desaturase 1 polymorphism, marine fish oil intake and the risk of oral squamous cell carcinoma: A case-control study].

OBJECTIVE: To evaluate the independent and joint effects of FADS1 polymorphism and fish oil intake on oral squamous cell carcinoma( OSCC). METHODS: A case-control study was conducted with 259 newly diagnosed primary OSCC patients and538 controls frequency-matched by sex and age in Fujian from September 2010 to September 2014. Data on demographics and dietary habits such as marine fish oil intake were collected using a structure questionnaire. FADS1 rs174549 genotype was determined using Taq Man genotyping assays. Unconditional logistic regression was used to the oddsratios( ORs) and their 95% confidence intervals( CI) of FADS1 polymorphism and fish oil intake for OSCC. RESULTS: FADS1 rs174549 AA genotype was associated with decreased risk of OSCC( codominant model: OR = 0. 53, 95% CI 0. 33-0. 85; recessive model: OR = 0. 57, 95% CI 0. 38-0. 87). Compared with those who non-intake marine fish oil, regularly intake of marine fish oil decreased the risk of OSCC( OR = 0. 54, 95%CI: 0. 32-0. 91). Moreover, a multiplicative interaction between FADS1 rs174549 polymorphism and marine fish oil intake for oral cancer( OR_(multiplicative)= 0. 31, 95% CI0. 11-0. 87). CONCLUSION: FADS1 rs174549 polymorphism and marine fish oil intake may be independent protective factors for OSCC with a gene-diet multiplicative interaction.

Compensatory induction of Fads1 gene expression in heterozygous Fads2-null mice and by diet with a high n-6/n-3 PUFA ratio.

In mammals, because they share a single synthetic pathway, n-6/n-3 ratios of dietary PUFAs impact tissue arachidonic acid (ARA) and DHA content. Likewise, SNPs in the human fatty acid desaturase (FADS) gene cluster impact tissue ARA and DHA. Here we tested the feasibility of using heterozygous Fads2-null-mice (HET) as an animal model of human FADS polymorphisms. WT and HET mice were fed diets with linoleate/α-linolenate ratios of 1:1, 7:1, and 44:1 at 7% of diet. In WT liver, ARA and DHA in phospholipids varied >2× among dietary groups, reflecting precursor ratios. Unexpectedly, ARA content was only <10% lower in HET than in WT livers, when fed the 44:1 diet, likely due to increased Fads1 mRNA in response to reduced Fads2 mRNA in HET. Consistent with the RNA data, C20:3n-6, which is elevated in minor FADS haplotypes in humans, was lower in HET than WT. Diet and genotype had little effect on brain PUFAs even though brain Fads2 mRNA was low in HET. No differences in cytokine mRNA were found among groups under unstimulated conditions. In conclusion, differential PUFA profiles between HET mice and human FADS SNPs suggest low expression of both FADS1 and 2 genes in human minor haplotypes.

Reduced Expression of FADS1 Predicts Worse Prognosis in Non-Small-Cell Lung Cancer.

OBJECTIVE: Fatty acid desaturase 1 is a member of the fatty acid desaturase, which is related to a number of diseases. However, its role in cancers remains unclear. This study was to explore the clinical importance of FADS1 expression in non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Immunochemistry was used to evaluate FADS1 expressions in 216 paraffin-embedded specimens. The expression of FADS1 was divided into high and low groups. The clinical and prognostic significance of FADS1 expression was analyzed statistically by Kaplan-Meier estimate and Cox regression model. RESULTS: FADS1 overexpressed in normal bronchial mucosa compared with non-small-cell lung cancer. Reduced FADS1 expression was associated with tumor size (P=0.023) and histological grade (P<0.0001). Patients with lower expression of FADS1 had shorter overall survival and disease free survival (P=0.001 and P=0.002). Multivariate analysis showed FADS1 expression was an independent prognostic factor in NSCLC (P=0.011). CONCLUSION: Reduced expression of FADS1 suggests pessimistic prognosis for NSCLC patients. Further studies are warranted.

Restriction of dietary protein does not promote hepatic lipogenesis in lean or fatty pigs.

The influence of genotype (lean v. fatty) and dietary protein level (normal v. reduced) on plasma metabolites, hepatic fatty acid composition and mRNA levels of lipid-sensitive factors is reported for the first time, using the pig as an experimental model. The experiment was conducted on forty entire male pigs (twenty lean pigs of Large White×Landrace×Pietrain cross-breed and twenty fatty pigs of Alentejana purebreed) from 60 to 93 kg of live weight. Each pig genotype was divided into two subgroups, which were fed the following diets: a normal protein diet (NPD) equilibrated for lysine (17·5 % crude protein and 0·7 % lysine) and a reduced protein diet (RPD) not equilibrated for lysine (13·1 % crude protein and 0·4 % lysine). The majority of plasma metabolites were affected by genotype, with lean pigs having higher contents of lipids, whereas fatty pigs presented higher insulin, leptin and urea levels. RPD increased plasma TAG, free fatty acids and VLDL-cholesterol compared with NPD. Hepatic total lipids were higher in fatty pigs than in the lean genotype. RPD affected hepatic fatty acid composition but had a slight influence on gene expression levels in the liver. Sterol regulatory element-binding factor 1 was down-regulated by RPD, and fatty acid desaturase 1 (FADS1) and fatty acid binding protein 4 (FABP4) were affected by the interaction between genotype and diet. In pigs fed RPD, FADS1 was up-regulated in the lean genotype, whereas FABP4 increased in the fatty genotype. Although there is a genotype-specific effect of dietary protein restriction on hepatic lipid metabolism, lipogenesis is not promoted in the liver of lean or fatty pigs.

FADS2 genotype regulates delta-6 desaturase activity and inflammation in human adipose tissue.

Obesity is associated with disturbed lipid metabolism and low-grade inflammation in tissues. The aim of this study was to investigate the association between FA metabolism and adipose tissue (AT) inflammation in the Kuopio Obesity Surgery study. We investigated the association of surgery-induced weight loss and FA desaturase (FADS)1/2 genotypes with serum and AT FA profile and with AT inflammation, measured as interleukin (IL)-1ß and NFκB pathway gene expression, in order to find potential gene-environment interactions. We demonstrated an association between serum levels of saturated and polyunsaturated n-6 FAs, and estimated enzyme activities of FADS1/2 genes with IL-1ß expression in AT both at baseline and at follow-up. Variation in the FADS1/2 genes associated with IL-1ß and NFκB pathway gene expression in SAT after weight reduction, but not at baseline. In addition, the FA composition in subcutaneous and visceral fat correlated with serum FAs, and the associations between serum PUFAs and estimated D6D enzyme activity with AT inflammation were also replicated with corresponding AT FAs and AT inflammation. We conclude that the polymorphism in FADS1/2 genes associates with FA metabolism and AT inflammation, leading to an interaction between weight loss and FADS1/2 genes in the regulation of AT inflammation.

Variation in the FADS1/2 gene cluster alters plasma n-6 PUFA and is weakly associated with hsCRP levels in healthy young adults.

INTRODUCTION: Past research has reported that single nucleotide polymorphisms (SNPs) in fatty acid desaturase 1 and 2 (FADS1/2) can influence plasma fatty acid (FA) profiles. Changes in FA profiles are known to influence inflammatory processes; therefore both FA and SNPs in FADS1/2 may affect inflammation. The goals of this study were to (i) examine the relationships between individual n-6 FA and estimates of FA desaturation with circulating high sensitivity C-reactive protein (hsCRP) levels, and (ii) determine whether SNPs in FADS1/2 are associated with changes in hsCRP. METHODS: FA and hsCRP were measured in fasted plasma samples from 878 healthy young adults (20-29yrs). Circulating levels of plasma linoleic (LA), γ-linolenic (GLA), dihomo-γ-linolenic (DGLA) and arachidonic (AA) acids were measured by gas chromatography and used to calculate desaturase indices for FADS1/2. Nineteen SNPs in FADS1/2 were genotyped in all subjects and six (rs174579, rs174593, rs174626, rs526126, rs968567 and rs17831757) were further analyzed. RESULTS: Significant inverse associations were found between LA and hsCRP (p=8.55×10(-9)) and the FADS1 desaturase index and hsCRP (p=4.41×10(-6)). A significant positive association was found between DGLA and hsCRP (p=9.10×10(-11)). Several SNPs were associated with circulating levels of individual FA and desaturase indices, with minor allele carriers having lower AA levels and reduced desaturase indices. A single SNP in FADS2 (rs526126) was weakly associated with hsCRP (p=0.05). CONCLUSIONS: This study highlights the relationships between FA and hsCRP, and confirms that FA are strongly influenced by SNPs in FADS1/2. Furthermore, we found weak evidence that SNPs in FADS1/2 may influence hsCRP levels in young adults.