The Experts below are selected from a list of 1563 Experts worldwide ranked by ideXlab platform
David M Mutch - One of the best experts on this subject based on the ideXlab platform.
-
FADS1 genotype is distinguished by human subcutaneous adipose tissue fatty acids, but not inflammatory gene expression
International Journal of Obesity, 2018Co-Authors: Shannon L. Klingel, Armand Valsesia, Arne Astrup, Marie Kunesova, Wim H. M. Saris, Dominique Langin, Nathalie Viguerie, David M MutchAbstract:Single nucleotide polymorphisms (SNPs) in FADS1/FADS2 genes are associated with changes in serum and tissue polyunsaturated fatty acid (PUFA) content. PUFA regulate inflammatory signaling pathways in adipose tissue; however, the effect of SNPs in FADS1/FADS2 on adipose tissue inflammation is equivocal. The present study examined if SNPs in FADS1/FADS2 modify human subcutaneous adipose tissue (SAT) fatty acid profiles and the expression of genes associated with inflammation/immune function, lipid metabolism, and cellular differentiation. SAT fatty acids and the expression of 117 genes were measured in 174 men and women from the DiOGenes Study using gas chromatography and qRT-PCR, respectively. Associations between fatty acids, gene expression, and SNPs in FADS1/FADS2 were investigated by linear regression and multivariate analysis. Four SNPs (rs174537, rs174546, rs174556, rs174601) in FADS1/FADS2 were significantly associated with SAT fatty acids. All SNPs were in high linkage disequilibrium with the commonly reported rs174537 SNP in FADS1. Minor allele carriers for rs174537 (GT+TT) had reduced 20:4n-6 (p = 1.74E−5), lower delta-5 desaturase enzyme activity (p = 2.09E−9), and lower FADS1 gene expression (p = 0.03) compared to major GG carriers. Multivariate analysis revealed that 20:4n-6 and 20:3n-6 explained ~19% of the variance between rs174537 genotypes, while gene expression explained
-
polyunsaturated fatty acid regulation of adipocyte FADS1 and fads2 expression and function
Obesity, 2015Co-Authors: Jessica C Ralston, Sarthak Matravadia, Nicholas Gaudio, Graham P Holloway, David M MutchAbstract:Objective Polyunsaturated fatty acids (PUFAs) regulate fatty acid desaturase (FADS1, FADS2) expression in the liver; however, it is unknown whether PUFAs regulate FADS in adipocytes. This is important to study considering reports that link altered desaturase activity with adipose tissue PUFA profiles, body weight, and whole-body glucose homeostasis. Therefore, the present study aimed to determine the direct effects of PUFAs on FADS expression in differentiated 3T3-L1 adipocytes. Methods Differentiated 3T3-L1 adipocytes were treated with either α-linolenic (ALA), linoleic (LA), eicosapentaenoic (EPA), or arachidonic acid (AA). Gene expression, protein abundance, and cellular PUFA content were analyzed by real-time RT-PCR, Western blotting, and gas chromatography, respectively. Results FADS1 and Fads2 gene expression was reduced by EPA and AA, but not ALA or LA. Reductions in gene expression were reflected in FADS2 protein levels, but not FADS1. Treating cells with ALA and LA led to significant increases in the cellular content of downstream PUFAs. Neither ALA nor EPA changed docosahexaenoic acid content. Conclusions Differentiated 3T3-L1 adipocytes have a functional FADS pathway that can be regulated by PUFA. Therefore, this common adipocyte model is suitable to study dietary regulation of the FADS pathway.
-
the role of FADS1 2 polymorphisms on cardiometabolic markers and fatty acid profiles in young adults consuming fish oil supplements
Nutrients, 2014Co-Authors: Kaitlin Roke, David M MutchAbstract:Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 (n-3) fatty acids (FAs) known to influence cardiometabolic markers of health. Evidence suggests that single nucleotide polymorphisms (SNPs) in the fatty acid desaturase 1 and 2 (FADS1/2) gene cluster may influence an individual’s response to n-3 FAs. This study examined the impact of a moderate daily dose of EPA and DHA fish oil supplements on cardiometabolic markers, FA levels in serum and red blood cells (RBC), and whether these endpoints were influenced by SNPs in FADS1/2. Young adults consumed fish oil supplements (1.8 g total EPA/DHA per day) for 12 weeks followed by an 8-week washout period. Serum and RBC FA profiles were analyzed every two weeks by gas chromatography. Two SNPs were genotyped: rs174537 in FADS1 and rs174576 in FADS2. Participants had significantly reduced levels of blood triglycerides (−13%) and glucose (–11%) by week 12; however, these benefits were lost during the washout period. EPA and DHA levels increased significantly in serum (+250% and +51%, respectively) and RBCs (+132% and +18%, respectively) within the first two weeks of supplementation and remained elevated throughout the 12-week period. EPA and DHA levels in RBCs only (not serum) remained significantly elevated (+37% and +24%, respectively) after the washout period. Minor allele carriers for both SNPs experienced greater increases in RBC EPA levels during supplementation; suggesting that genetic variation at this locus can influence an individual’s response to fish oil supplements.
-
The Role of FADS1/2 Polymorphisms on Cardiometabolic Markers and Fatty Acid Profiles in Young Adults Consuming Fish Oil Supplements
Nutrients, 2014Co-Authors: Kaitlin Roke, David M MutchAbstract:Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 (n-3) fatty acids (FAs) known to influence cardiometabolic markers of health. Evidence suggests that single nucleotide polymorphisms (SNPs) in the fatty acid desaturase 1 and 2 (FADS1/2) gene cluster may influence an individual’s response to n-3 FAs. This study examined the impact of a moderate daily dose of EPA and DHA fish oil supplements on cardiometabolic markers, FA levels in serum and red blood cells (RBC), and whether these endpoints were influenced by SNPs in FADS1/2. Young adults consumed fish oil supplements (1.8 g total EPA/DHA per day) for 12 weeks followed by an 8-week washout period. Serum and RBC FA profiles were analyzed every two weeks by gas chromatography. Two SNPs were genotyped: rs174537 in FADS1 and rs174576 in FADS2. Participants had significantly reduced levels of blood triglycerides (−13%) and glucose (–11%) by week 12; however, these benefits were lost during the washout period. EPA and DHA levels increased significantly in serum (+250% and +51%, respectively) and RBCs (+132% and +18%, respectively) within the first two weeks of supplementation and remained elevated throughout the 12-week period. EPA and DHA levels in RBCs only (not serum) remained significantly elevated (+37% and +24%, respectively) after the washout period. Minor allele carriers for both SNPs experienced greater increases in RBC EPA levels during supplementation; suggesting that genetic variation at this locus can influence an individual’s response to fish oil supplements.
-
variation in the FADS1 2 gene cluster alters plasma n 6 pufa and is weakly associated with hscrp levels in healthy young adults
Prostaglandins Leukotrienes and Essential Fatty Acids, 2013Co-Authors: Kaitlin Roke, Jessica C Ralston, Daiva E Nielsen, Alaa Badawi, Ahmed Elsohemy, David W L, Salma A Abdelmagid, David M MutchAbstract:Abstract 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.
Joachim Heinrich - One of the best experts on this subject based on the ideXlab platform.
-
FADS1 and fads2 polymorphisms modulate fatty acid metabolism and dietary impact on health
Annual Review of Nutrition, 2019Co-Authors: Berthold Koletzko, Eva Reischl, Joachim Heinrich, Conny Tanjung, Ines Gonzalezcasanova, Usha Ramakrishnan, Suzanne Meldrum, Karen Simmer, Hans DemmelmairAbstract:Variants in the FADS gene cluster modify the activity of polyunsaturated fatty acid (PUFA) desaturation and the lipid composition in human blood and tissue. FADS variants have been associated with ...
-
role of FADS1 and fads2 polymorphisms in polyunsaturated fatty acid metabolism
Metabolism-clinical and Experimental, 2010Co-Authors: Claudia Glaser, Joachim Heinrich, Berthold KoletzkoAbstract:Tissue availability of polyunsaturated fatty acids (PUFAs) depends on dietary intake and metabolic turnover and has a major impact on human health. Strong associations between variants in the human genes fatty acid desaturase 1 (FADS1, encoding Δ-5 desaturase) and fatty acid desaturase 2 (FADS2, encoding Δ-6 desaturase) and blood levels of PUFAs and long-chain PUFAs (LC-PUFAs) have been reported. The most significant associations and the highest proportion of genetically explained variability (28%) were found for arachidonic acid (20:4n-6), the main precursor of eicosanoids. Subjects carrying the minor alleles of several single nucleotide polymorphisms had a lower prevalence of allergic rhinitis and atopic eczema. Therefore, blood levels of PUFAs and LC-PUFAs are influenced not only by diet, but to a large extent also by genetic variants common in a European population. These findings have been replicated in independent populations. Depending on genetic variants, requirements of dietary PUFA or LC-PUFA intakes to achieve comparable biological effects may differ. We recommend including analyses of FADS1 and FADS2 polymorphism in future cohort and intervention studies addressing biological effects of PUFAs and LC-PUFAs.
-
genetic variants of the FADS1 fads2 gene cluster as related to essential fatty acid metabolism
Current Opinion in Lipidology, 2010Co-Authors: Eva Lattka, Berthold Koletzko, Thomas Illig, Joachim HeinrichAbstract:Purpose of reviewThe delta-5 and delta-6 desaturases have long been known to be important enzymes in the endogenous formation of long-chain polyunsaturated fatty acids (LC-PUFAs). Cloning of the coding sequences and chromosomal localization of the desaturase encoding genes fatty acid desaturase 1 an
-
evidence for an association between genetic variants of the fatty acid desaturase 1 fatty acid desaturase 2 FADS1 fads2 gene cluster and the fatty acid composition of erythrocyte membranes
British Journal of Nutrition, 2008Co-Authors: Peter Rzehak, Linda Schaeffer, Norman Klopp, Joachim Heinrich, Sebastian Hoff, Giinther Wolfram, Thomas Illig, J LinseisenAbstract:The present study gives further evidence for the recently found association between variants of the fatty acid desaturase 1 fatty acid desaturase 2(FADS1 FADS2) gene cluster and PUFA in blood phospholipids and explores this association for cellular fatty acids in erythrocyte membranes. In asubgroup of adults participating in the Bavarian Nutrition Survey II, a cross-sectional population-based study conducted in Bavaria, Germany,allelic variation in three selected loci of the FADS1 FADS2 gene cluster was analysed and used for haplotype construction. Associations withplasma phospholipid PUFA (n 163) and PUFA in erythrocyte membranes (n 535) were investigated by regression analysis. All haplotypes ofthe original five-loci haplotypes of our previous study could be replicated. In addition, associations with serum phospholipid PUFA were confirmedin the present data set. Although less pronounced, associations between FADS1 FADS2 haplotypes and PUFA in erythrocyte membranes, parti-cularly arachidonic and dihomo-g-linolenic acid, could be established. We provide the first replication of the association of the FADS1 FADS2gene cluster with PUFA in blood phospholipids. For the first time, such associations were also shown for PUFA in cell membranes.FADS1 FADS2 gene cluster: Polyunsaturated fatty acids: Blood phospholipids: Erythrocyte membranes: Bavarian Nutrition Survey II
-
common genetic variants of the FADS1 fads2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids
Human Molecular Genetics, 2006Co-Authors: Linda Schaeffer, Berthold Koletzko, Hans Demmelmair, Thomas Illig, Henning Gohlke, Martina Muller, Iris M Heid, Lyle J Palmer, Iris Kompauer, Joachim HeinrichAbstract:Fatty acid composition in membranes plays an important role in cellular processes and has shown to be associated with the aetiology of several complex diseases in humans. We report strong associations between variants in the human delta-5 and delta-6 desaturase genes FADS1 FADS2 and fatty acid composition in serum phospholipids. Eighteen polymorphisms located in this gene cluster were genotyped in 727 adults from Erfurt, a German centre of the European Community Respiratory Health Survey. The cluster is located at chromosome 11q12-11q13.1, a region repeatedly found to be linked with atopy and other complex diseases. Polymorphisms and statistically reconstructed haplotypes of FADS1 and the upstream region of FADS2 showed strongest associations with the level of the direct precursor of inflammatory eicosanoids, the n-6 fatty acid arachidonic acid (C20:4n-6), also strong associations with levels of the n-6 fatty acids C18:2n-6, C18:3n-6, C20:2n-6, C20:3n-6, C22:4n-6 and of the n-3 fatty acids C18:3n-3, C20:5n-3 and C22:5n-3 (P-values < 1.0 x 10(-13)). Carriers of the rare alleles of several SNPs and their respective haplotypes had a lower prevalence of allergic rhinitis and atopic eczema. No association was found for total and specific IgE levels.
Kaitlin Roke - One of the best experts on this subject based on the ideXlab platform.
-
exploration of the perceived and actual benefits of omega 3 fatty acids and the impact of FADS1 and fads2 genetic information on dietary intake and blood levels of epa and dha
Applied Physiology Nutrition and Metabolism, 2017Co-Authors: Kaitlin RokeAbstract:From a global health perspective, increased intake of omega-3 fatty acids (FAs), in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are beneficial for human health. However, the consumption of EPA- and DHA-rich foods such as fatty fish is low in the Western diet. Therefore, finding new ways to motivate people to increase their consumption of omega-3 FAs is essential. To find effective ways to motivate individuals, understanding people’s awareness of omega-3 FAs and how they obtain their knowledge about nutrition and health is critical. Consequently, we developed an online survey to assess awareness and self-reported intake of omega-3 FAs and supplements in young adults. EPA and DHA are also produced endogenously to a limited extent through a pathway regulated by fatty acid desaturase 1 and 2 (FADS1 and FADS2) genes. Of relevance, single nucleotide polymorphisms (SNPs) in the FADS genes influence levels of omega-3 FAs, where minor allele carriers have lower levels compared with major...
-
the role of FADS1 2 polymorphisms on cardiometabolic markers and fatty acid profiles in young adults consuming fish oil supplements
Nutrients, 2014Co-Authors: Kaitlin Roke, David M MutchAbstract:Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 (n-3) fatty acids (FAs) known to influence cardiometabolic markers of health. Evidence suggests that single nucleotide polymorphisms (SNPs) in the fatty acid desaturase 1 and 2 (FADS1/2) gene cluster may influence an individual’s response to n-3 FAs. This study examined the impact of a moderate daily dose of EPA and DHA fish oil supplements on cardiometabolic markers, FA levels in serum and red blood cells (RBC), and whether these endpoints were influenced by SNPs in FADS1/2. Young adults consumed fish oil supplements (1.8 g total EPA/DHA per day) for 12 weeks followed by an 8-week washout period. Serum and RBC FA profiles were analyzed every two weeks by gas chromatography. Two SNPs were genotyped: rs174537 in FADS1 and rs174576 in FADS2. Participants had significantly reduced levels of blood triglycerides (−13%) and glucose (–11%) by week 12; however, these benefits were lost during the washout period. EPA and DHA levels increased significantly in serum (+250% and +51%, respectively) and RBCs (+132% and +18%, respectively) within the first two weeks of supplementation and remained elevated throughout the 12-week period. EPA and DHA levels in RBCs only (not serum) remained significantly elevated (+37% and +24%, respectively) after the washout period. Minor allele carriers for both SNPs experienced greater increases in RBC EPA levels during supplementation; suggesting that genetic variation at this locus can influence an individual’s response to fish oil supplements.
-
The Role of FADS1/2 Polymorphisms on Cardiometabolic Markers and Fatty Acid Profiles in Young Adults Consuming Fish Oil Supplements
Nutrients, 2014Co-Authors: Kaitlin Roke, David M MutchAbstract:Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 (n-3) fatty acids (FAs) known to influence cardiometabolic markers of health. Evidence suggests that single nucleotide polymorphisms (SNPs) in the fatty acid desaturase 1 and 2 (FADS1/2) gene cluster may influence an individual’s response to n-3 FAs. This study examined the impact of a moderate daily dose of EPA and DHA fish oil supplements on cardiometabolic markers, FA levels in serum and red blood cells (RBC), and whether these endpoints were influenced by SNPs in FADS1/2. Young adults consumed fish oil supplements (1.8 g total EPA/DHA per day) for 12 weeks followed by an 8-week washout period. Serum and RBC FA profiles were analyzed every two weeks by gas chromatography. Two SNPs were genotyped: rs174537 in FADS1 and rs174576 in FADS2. Participants had significantly reduced levels of blood triglycerides (−13%) and glucose (–11%) by week 12; however, these benefits were lost during the washout period. EPA and DHA levels increased significantly in serum (+250% and +51%, respectively) and RBCs (+132% and +18%, respectively) within the first two weeks of supplementation and remained elevated throughout the 12-week period. EPA and DHA levels in RBCs only (not serum) remained significantly elevated (+37% and +24%, respectively) after the washout period. Minor allele carriers for both SNPs experienced greater increases in RBC EPA levels during supplementation; suggesting that genetic variation at this locus can influence an individual’s response to fish oil supplements.
-
variation in the FADS1 2 gene cluster alters plasma n 6 pufa and is weakly associated with hscrp levels in healthy young adults
Prostaglandins Leukotrienes and Essential Fatty Acids, 2013Co-Authors: Kaitlin Roke, Jessica C Ralston, Daiva E Nielsen, Alaa Badawi, Ahmed Elsohemy, David W L, Salma A Abdelmagid, David M MutchAbstract:Abstract 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.
-
Variation in the FADS1/2 gene cluster alters plasma n−6 PUFA and is weakly associated with hsCRP levels in healthy young adults
Prostaglandins Leukotrienes and Essential Fatty Acids, 2013Co-Authors: Kaitlin Roke, Jessica C Ralston, Daiva E Nielsen, Alaa Badawi, Salma A Abdelmagid, Ahmed El-sohemy, David M MutchAbstract:Abstract 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.
Ichiro Tatsuno - One of the best experts on this subject based on the ideXlab platform.
-
fatty acid desaturase 2 is up regulated by the treatment with statin through geranylgeranyl pyrophosphate dependent rho kinase pathway in hepg2 cells
Scientific Reports, 2019Co-Authors: Shou Tanaka, Masahiro Ohira, Tomoaki Tanaka, Noriko Ishihara, Sawako Suzuki, Yasuhiro Watanabe, Daiji Nagayama, Atsuhito Saiki, Takashi Yamaguchi, Ichiro TatsunoAbstract:Statins have been reported to increase the plasma concentration of arachidonic acid (AA), an omega-6 long chain polyunsaturated fatty acid (LCPUFA) in several clinical studies indicating that statins affect the endogenous synthesis of LCUFAs. In the present study, we investigated the roles of the intrinsic mevalonate cascade and Rho-dependent pathway in LCPUFA synthesis, especially focusing on fatty acid desaturases (Fads) 2, using the human hepatocellular carcinoma cell line HepG2. Cell number and the activity of caspase-3 and 7 (caspase-3/7) was measured using a commercial kit. Gene expression was analyzed by quantitative real-time PCR. Protein expression was detected by Western blot analysis. Atorvastatin decreased cell viability and increased caspase-3/7 activity in a dose-dependent manner. At lower concentrations, atorvastatin stimulated both mRNA and protein expression of Fads2, and increased mRNA expression of FADS1 and ELVOL5. Both mevalonate and geranylgeranyl-pyrophosphate (GGPP), but not cholesterol, fully reversed atorvastatin-induced upregulation of Fads2, and mevalonate-effected reversal was inhibited by treatment with the Rho-associated protein kinase inhibitor Y-27632. These data clearly demonstrated that in human HepG2 cells, statins affect the endogenous synthesis of LCPUFAs by regulation of not only Fads2, but also FADS1 and Elovl5, through the GGPP-dependent Rho kinase pathway.
-
atorvastatin increases fatty acid desaturases fadss and elongation of very long chain fatty acids elovls through geranylgeranyl pyrophosphate ggpp dependent rho kinase pathway in hepg2 cells
Diabetes, 2018Co-Authors: Ichiro Tatsuno, Shou Tanaka, Noriko IshiharaAbstract:Background: The plasma concentration of arachidonic acid, one of the omega-6 long-chain polyunsaturated fatty acids (LCPUFAs), was increased by the treatment of statin in several clinical studies indicating that statin affects the endogenous synthesis of LCPUFAs, which is regulated by the action of the fatty acid desaturases (FADSs) and elongation of very long-chain fatty acids (ELOVLs). Aims: We investigated the roles of the intrinsic mevalonate cascade and rho-dependent pathway in the statin-induced regulation of these desaturases and elongases using human hepatocellular carcinoma cell line HepG2 cells. Methods: Cell viability was assessed by measuring mitochondrial activity of WST-8, and the activity of caspase-3 and -7 (caspase-3/7) was measured. Gene expression was analyzed by quantitative real-time PCR. Protein expressions were detected by Western blot analysis. Results: Although atorvastatin decreased the cell viability with increasing activity of caspase-3/7 in a dose-dependent manner, both mRNA and protein expression of FADS2 were stimulated by atorvastatin at lower dose of 12.5 and 25 uM, where mRNA expression of FADS1 and Elovl5 also increased. Both mevalonate and geranylgeranyl-pyrophosphate (GGPP), not cholesterol, fully restored the atorvastatin-induced inhibition of cell viability, and the atorvastatin-induced upregulation of mRNA and protein of FADS2. The Rho-associated protein kinase (ROCK) inhibitor Y-27632 inhibits the restoration of mevalonate and GGPP. Both EPA and DHA, but not AA, significantly suppressed the atorvastatin-induced upregulation of gene expression of FADS1, FADS2 and Elovl5. Conclusions: These data demonstrated that statin may affect the endogenous synthesis of LCPUFAs by the regulation of these desaturases and elongases through GGPP-dependent rho kinase pathway in HepG2 cells. Disclosure I. Tatsuno: None. S. Tanaka: None. N. Ishihara: None.
-
atorvastatin increases FADS1 fads2 and elovl5 gene expression via the geranylgeranyl pyrophosphate dependent rho kinase pathway in 3t3 l1 cells
Molecular Medicine Reports, 2017Co-Authors: Noriko Ishihara, Tomoaki Tanaka, Sawako Suzuki, Shou Tanaka, Yasuhiro Watanabe, Daiji Nagayama, Atsuhito Saiki, Ichiro TatsunoAbstract:Numerous clinical studies have reported that statins increase the plasma concentration of arachidonic acid, which is an ω-6 long-chain polyunsaturated fatty acid (LCPUFA), and decrease the concentrations of eicosapentaenoic acid and docosahexaenoic acid, which are ω‑3 LCPUFAs. These findings indicate that statins may affect the endogenous synthesis of LCPUFAs, which is regulated by fatty acid desaturases (FADSs) and elongation of very long‑chain fatty acids proteins (ELOVLs). The present study aimed to investigate the roles of the intrinsic mevalonate cascade and Rho‑dependent pathway in statin‑induced regulation of these desaturases and elongases, as well as cell viability using mouse 3T3‑L1 cells. mRNA expression was analyzed by quantitative polymerase chain reaction. Treatment with atorvastatin decreased cell viability and increased the mRNA expression levels of FADS1, Fads2 and ELOVL fatty acid elongase 5 (Elovl5) in a dose‑dependent manner. Mevalonate and geranylgeranyl pyrophosphate (GGPP), but not cholesterol, fully reversed the atorvastatin‑induced downregulation of cell viability and upregulation of gene expression; however, mevalonate itself did not affect cell viability and gene expression. The Rho‑associated protein kinase inhibitor Y‑27632 inhibited the mevalonate‑ and GGPP‑mediated reversal of atorvastatin‑induced upregulation of FADS1, Fads2 and Elovl5. These findings indicated that statins may affect the endogenous synthesis of LCPUFAs by regulating FADS1, Fads2 and Elovl5 gene expression via the GGPP‑dependent Rho kinase pathway in mouse 3T3-L1 cells.
Nathalie Viguerie - One of the best experts on this subject based on the ideXlab platform.
-
FADS1 genotype is distinguished by human subcutaneous adipose tissue fatty acids but not inflammatory gene expression
International Journal of Obesity, 2019Co-Authors: Shannon L. Klingel, Armand Valsesia, Arne Astrup, Marie Kunesova, Wim H. M. Saris, Dominique Langin, Nathalie ViguerieAbstract:Single nucleotide polymorphisms (SNPs) in FADS1/FADS2 genes are associated with changes in serum and tissue polyunsaturated fatty acid (PUFA) content. PUFA regulate inflammatory signaling pathways in adipose tissue; however, the effect of SNPs in FADS1/FADS2 on adipose tissue inflammation is equivocal. The present study examined if SNPs in FADS1/FADS2 modify human subcutaneous adipose tissue (SAT) fatty acid profiles and the expression of genes associated with inflammation/immune function, lipid metabolism, and cellular differentiation. SAT fatty acids and the expression of 117 genes were measured in 174 men and women from the DiOGenes Study using gas chromatography and qRT-PCR, respectively. Associations between fatty acids, gene expression, and SNPs in FADS1/FADS2 were investigated by linear regression and multivariate analysis. Four SNPs (rs174537, rs174546, rs174556, rs174601) in FADS1/FADS2 were significantly associated with SAT fatty acids. All SNPs were in high linkage disequilibrium with the commonly reported rs174537 SNP in FADS1. Minor allele carriers for rs174537 (GT+TT) had reduced 20:4n-6 (p = 1.74E−5), lower delta-5 desaturase enzyme activity (p = 2.09E−9), and lower FADS1 gene expression (p = 0.03) compared to major GG carriers. Multivariate analysis revealed that 20:4n-6 and 20:3n-6 explained ~19% of the variance between rs174537 genotypes, while gene expression explained <7%. Receiver operating characteristic (ROC) curves indicated that rs174537 genotype can be distinguished with SAT fatty acids (AUC = 0.842), but not gene expression (AUC = 0.627). No differences in SAT inflammatory gene expression were observed between rs174537 genotypes. SAT 20:3n-6 levels were positively correlated with the expression of several inflammatory genes, and inversely correlated with FADS1 expression. This study showed that FADS1 genotype is distinguished by SAT fatty acid profiles, but not inflammatory gene expression.
-
FADS1 genotype is distinguished by human subcutaneous adipose tissue fatty acids, but not inflammatory gene expression
International Journal of Obesity, 2018Co-Authors: Shannon L. Klingel, Armand Valsesia, Arne Astrup, Marie Kunesova, Wim H. M. Saris, Dominique Langin, Nathalie Viguerie, David M MutchAbstract:Single nucleotide polymorphisms (SNPs) in FADS1/FADS2 genes are associated with changes in serum and tissue polyunsaturated fatty acid (PUFA) content. PUFA regulate inflammatory signaling pathways in adipose tissue; however, the effect of SNPs in FADS1/FADS2 on adipose tissue inflammation is equivocal. The present study examined if SNPs in FADS1/FADS2 modify human subcutaneous adipose tissue (SAT) fatty acid profiles and the expression of genes associated with inflammation/immune function, lipid metabolism, and cellular differentiation. SAT fatty acids and the expression of 117 genes were measured in 174 men and women from the DiOGenes Study using gas chromatography and qRT-PCR, respectively. Associations between fatty acids, gene expression, and SNPs in FADS1/FADS2 were investigated by linear regression and multivariate analysis. Four SNPs (rs174537, rs174546, rs174556, rs174601) in FADS1/FADS2 were significantly associated with SAT fatty acids. All SNPs were in high linkage disequilibrium with the commonly reported rs174537 SNP in FADS1. Minor allele carriers for rs174537 (GT+TT) had reduced 20:4n-6 (p = 1.74E−5), lower delta-5 desaturase enzyme activity (p = 2.09E−9), and lower FADS1 gene expression (p = 0.03) compared to major GG carriers. Multivariate analysis revealed that 20:4n-6 and 20:3n-6 explained ~19% of the variance between rs174537 genotypes, while gene expression explained
