Delta 5-desaturase activity in liver and brain microsomes during development of the pig.
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ABSTRACT:
SUBMITTER: Clandinin MT
PROVIDER: S-EPMC1144936 | biostudies-other | 1985 May
REPOSITORIES: biostudies-other
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Project description:Microsomes isolated from liver and brain tissue were assayed to examine transitions in metabolic capability to synthesize chain elongation-desaturation products of C18:2(9,12) during the perinatal development of the pig. Microsomal synthesis of trienes, tetraenes and pentaenes was compared for fetal, neonatal and postnatal piglets. Rates of synthesis of tetraenes and pentaenes by chain elongation-desaturation of C18:2(9,12) were greatest in liver. During the later half of gestation, the capability to synthesize tetraenes increased 2-3-fold on a per mg of microsomal protein basis. Increase in the capacity to synthesize tetraenes suggests a significant transition in the activity of delta 5 desaturase during the last half of gestation. For brain, synthesis of C22:5(4,7,10,13,16) from C18:2(9,12) was greatest at term. These observations indicate that in liver and brain the capability to chain elongate-desaturate C18:2(9,12) to longer chain homologues increases significantly during early development. It is suggested that during gestation the activity of the delta 5 desaturase limits synthesis of C20 and C22 homologues of C18:2(9,12). The metabolic conversion of C20 and C22 fatty acids by chain elongation of C20:4(5,8,11,14) does not appear to limit the synthesis of very long chain homologues of linoleic acid in fetal liver or brain.
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Project description:The effect of feeding semipurified diets enriched in linseed (rich in C18:3, omega 3 fatty acid) or fish (rich in C20:5, omega 3 and C22:6, omega 3 fatty acid) oil with and without cholesterol supplementation on the desaturation of linoleic acid (C18:2, omega 6) by rat liver microsomal fractions was investigated. Animals fed diets supplemented with beef tallow were used as equal-energy controls. Both linseed-oil and fish-oil diets, without added cholesterol, decrease conversion of C18:2, omega 6 fatty acid to gamma-linolenic acid (C18:3, omega 6). Reduction in delta 6-desaturation was significantly greater for animals fed the diet containing fish oil than with animals fed the linseed-oil diet. The major effect of cholesterol supplementation was to decrease the rate of desaturation of C18:2, omega 6, when fed in combination with the beef-tallow diet, whereas delta 6-desaturation was unaffected when cholesterol was fed along with diets high in omega 3 fatty acids (linseed oil or fish oil). The activity of the delta 6-desaturase in vitro is consistent with the fatty acid composition observed for the microsomal membranes on which this enzyme is localized. Dietary linseed oil and fish oil lowered the arachidonic (C20:4, omega 6) acid content of rat liver microsomes, with an accompanying increase in membrane eicosapentaenoic (C20:5, omega 3) and docosahexaenoic (C22:6, omega 3) acid content, in comparison with the group fed beef tallow. Inclusion of cholesterol into the beef-tallow or linseed-oil diets resulted in decreased membrane C20:4, omega 6-fatty-acid content, with concomitant increase in C18:2, omega 6-fatty-acid content. However, addition of cholesterol to the fish-oil diet did not alter the microsomal membrane content of C20:4, omega 6 fatty acid. Thus it is suggested that (1) the decrease in prostaglandin E2, thromboxane and prostacyclin levels generally observed after fish-oil consumption may be at least partly due to inhibition of C20:4, omega 6-fatty-acid synthesis from C18:2, omega 6 fatty acid; and (2) consumption of fish oil prevents the further decrease in C20:4, omega 6-fatty-acid levels by dietary cholesterol that is apparent when cholesterol is fed in combination with diets high in saturated fat or C18:3, omega 3 fatty acid.
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Project description:Recent studies have shown that a tumor-supportive microenvironment is characterized by high levels of pro-inflammatory and pro-angiogenic eicosanoids derived from omega-6 (n-6) arachidonic acid (AA). Although the metabolic pathways (COX, LOX, and P450) that generate these n-6 AA eicosanoids have been targeted, the role of endogenous AA production in tumorigenesis remains unexplored. Delta-6 desaturase (D6D) is the rate-limiting enzyme responsible for the synthesis of n-6 AA and increased D6D activity can lead to enhanced n-6 AA production. Here, we show that D6D activity is upregulated during melanoma and lung tumor growth and that suppressing D6D activity, either by RNAi knockdown or a specific D6D inhibitor, dramatically reduces tumor growth. Accordingly, the content of AA and AA-derived tumor-promoting metabolites is significantly decreased. Angiogenesis and inflammatory status are also reduced. These results identify D6D as a key factor for tumor growth and as a potential target for cancer therapy and prevention.
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2023-04-24 | PXD040040 | Pride
Project description: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)-1? and NF?B 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-1? expression in AT both at baseline and at follow-up. Variation in the FADS1/2 genes associated with IL-1? and NF?B 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.
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Project description:AimThe most common causes of variability in drug response include differences in drug metabolism, especially when the hepatic cytochrome P450 (CYP) enzymes are involved. The current study was conducted to assess the differences in CYP activities in human liver microsomes (HLM) of Chinese or Caucasian origin.MethodsThe metabolic capabilities of CYP enzymes in 30 Chinese liver microsomal samples were compared with those of 30 Caucasian samples utilizing enzyme kinetics. Phenacetin O-deethylation, coumarin 7-hydroxylation, bupropion hydroxylation, amodiaquine N-desethylation, diclofenac 4'-hydroxylation (S)-mephenytoin 4'-hydroxylation, dextromethorphan O-demethylation, chlorzoxazone 6-hydroxylation and midazolam 1'-hydroxylation/testosterone 6?-hydroxylation were used as probes for activities of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A, respectively. Mann-Whitney U test was used to assess the differences.ResultsThe samples of the two ethnic groups were not significantly different in cytochrome-b(5) concentrations but were significantly different in total CYP concentrations and NADPH-P450 reductase activity (P < 0.05). Significant ethnic differences in intrinsic clearance were observed for CYP1A2, CYP2C9, CYP2C19 and CYP2E1; the median values of the Chinese group were 54, 58, 26, and 35% of the corresponding values of the Caucasian group, respectively. These differences were associated with differences in Michaelis constant or maximum velocity. Despite negligible difference in intrinsic clearance, the Michaelis constant of CYP2B6 appeared to have a significant ethnic difference. No ethnic difference was observed for CYP2A6, CYP2C8, CYP2D6 and CYP3A.ConclusionsThese data extend our knowledge on the ethnic differences in CYP enzymes and will have implications for drug discovery and drug therapy for patients from different ethnic origins.
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