ALOX5 gene variants affect eicosanoid production and response to fish oil supplementation

Abstract

Eicosanoids, including leukotrienes (LT), are products of arachidonic acid (AA) metabolism that mediate infl ammation during infectious, allergic, and other infl ammatory diseases ( 1 ), including cardiovascular disease (CVD) ( 2 ). The ALOX5 gene encodes the 5-lipoxygenase (5-LO) enzyme, which acts with 5-lipoxygenase activating protein (FLAP) to catalyze the fi rst two steps in LT synthesis, the production of 5-hydroperoxyeicosatetraenoate (5-HpETE), followed by its conversion to LTA4 or its glutathione peroxidase-dependent conversion to 5-hydroxyeicosatetraenoate (5-HETE) ( 3 ). 5-HETE is a bioactive semistable metabolite that reversibly forms a lactone (5-hydroxy-6 dlactone) ( 4, 5 ) and is also converted by 5-hydroxyeicosanoid dehydrogenase (5-HEDH) to the active metabolite 5-oxo -ETE ( 6 ). LTA4 is unstable ( 7 ) , 5-oxo -ETE, 15-HETE, and 5,15-diHETE levels were higher in subjects homozygous for the ALOX5 promoter allele containing fi ve Sp1 element tandem repeats ("55" genotype) than in subjects with one deletion (d) (three or four repeats) and one common ("d5" genotype) allele or with two deletion ("dd") alleles. The EPA-derived metabolites 5-HEPE and 15-HEPE and the DHA-derived metabolite 17-HDoHE had similar associations with genotype and increased with supplementation; 5-HEPE and 15-HEPE increased, and 5-oxo -ETE decreased to a greater degree in the 55 than in the other genotypes. This differential eicosanoid response is consistent with the previously observed interaction of these variants with dietary intake of omega-3 fatty acids in predicting cardiovascular disease risk. -

Prepartal dietary energy level affects peripartal bovine blood neutrophil metabolic, antioxidant, and inflammatory gene expression

“…The leukotrienes play a role in PMNL adhesion and phago-cytosis (Evans et al, 1986;Kasirga et al, 1999), but their intracellular concentrations must be controlled to prevent cell damage. The fact that expression of LTA4H decreased after calving regardless of diet and that expression of LTC4S was slightly upregulated postcalving by feeding HE suggests that leukotriene production by PMNL might not be as physiologically relevant as the utilization of arachidonic acid for synthesis of prostaglandins and eicosanoids that can activate PPAR (Stephensen et al, 2011;Buckley et al, 2014). Direct measurement of prostaglandin and eicosanoid production will be helpful to validate this hypothesis.…”

“…Different genes are involved in the control of intracellular leukotriene concentrations, such as PLA2G4A (Holinstat et al, 2011), ALOX5 and ALOX5AP (Stephensen et al, 2011), and LTA4H and LTC4S. The leukotrienes play a role in PMNL adhesion and phago-cytosis (Evans et al, 1986;Kasirga et al, 1999), but their intracellular concentrations must be controlled to prevent cell damage.…”

“…Generation of arachidonic acid via key enzymes such as PLA2G4A (Funk, 2001) and ALOX5AP (Stephensen et al, 2011) is essential for the activation of NADPH oxidase (Pessach et al, 2001). In the current study, the upregulation of these 2 genes in HE cows suggests that, prepartum, the HE diet led to greater release of arachidonic acid from PMNL membranes and subsequent Figure 4.…”

Indomethacin Treatment Prevents High Fat Diet-induced Obesity and Insulin Resistance but Not Glucose Intolerance in C57BL/6J Mice

“…Plasma Oxylipins-Plasma samples were extracted using Oasis HLB solid phase extraction cartridges (Waters Corp., Milford, MA) as described previously (21). Analytes were eluted with methanol and ethyl acetate into 6 l of glycerol and subjected to vacuum evaporation, and the resulting glycerol plug was stored at Ϫ80°C.…”

Arachidonate 5-Lipoxygenase Gene Variants Affect Response to Fish Oil Supplementation by Healthy African Americans

“…Healthy adults 20-59 y of age who self-identified as African American, black, or of African ancestry were recruited into the study in Oakland, Davis, and Sacramento as previously described (19). Briefly, after an initial questionnaire and genotype assessment, potentially eligible participants were contacted to schedule an appointment for a screening blood draw to be used for a complete blood count, lipid panel, and chemistry panel.…”