Kegg Pathway: Arachidonic acid metabolism

KEGG ID: 00590

Reference Diagram

KEGG Diagram for Arachidonic acid metabolism

Rat

There are 53 IPI Records from this pathway found in Rattus norvegicus.

Location of Arachidonic acid metabolism proteins on Rat Genome

IPI Record Position
1: Alox12b 10:55917514-55926357
2: Alox15 10:57185939-57194388
3: Alox15b 10:55950975-55960565
4: Alox5 4:152610283-152657801
5: Cbr1 11:33787905-33790319
6: Cyp2b1 1:81780088-81853249
7: Cyp2b21 1:81658154-81687123
8: Cyp2b3 1:81185072-81185251
9: Cyp2c 1:243280474-243320945
10: Cyp2c12 :-
11: Cyp2c13 1:245142872-245149649
12: Cyp2c22 1:245298367-245329437
13: Cyp2c23 1:249204049-249228685
14: Cyp2c6 1:243840031-243896002
15: Cyp2c7 1:243702724-243752996
16: Cyp2e1 1:200918521-200928919
17: Cyp2j3 :-
18: Cyp2j4 5:116702370-116766813
19: Cyp4a1 5:135901624-135915753
20: Cyp4a10 :-
21: Cyp4a3 5:135767919-135772855
22: Cyp4a8 :-
23: Cyp4f1 7:13589662-13600856
24: Cyp4f4 7:13293080-13309416
25: Cyp4f5 7:13119551-13134015
26: Cyp4f6 7:13609104-13636290
27: Dhrs4 15:33609570-33621142
28: Ephx2 15:45497946-45556060
29: Ggt1 :-
30: Ggtl3 3:145987531-146010910
31: Ggtla1 :-
32: Gpx1 :-
33: Gpx2 6:99372734-99376109
34: Gpx3 10:40311162-40318659
35: Gpx4 7:11162739-11165252
36: Gpx6 17:51063818-51068013
37: Lta4h 7:30482213-30515062
38: Ltc4s 10:35786877-35788838
39: Pla2g10 10:26035-37273
40: Pla2g12a_predicted 2:227331064-227348076
41: Pla2g1b 12:42405475-42415189
42: Pla2g2a 5:157654294-157657361
43: Pla2g2c 5:157535999-157558206
44: Pla2g4a 13:64135734-64280815
45: Pla2g5 5:157619678-157640995
46: Pla2g6 7:117266784-117307172
47: Ptgds 3:3632683-3635642
48: Ptgds2 4:94611607-94636147
49: Ptges 3:9946194-9957540
50: Ptgis 3:158357021-158361906
51: Ptgs1 3:15343985-15364496
52: Ptgs2 13:64427282-64432982
53: Tbxas1 4:66502253-66677538

Mouse

There are 53 IPI Records from this pathway found in Mus musculus.

Location of Arachidonic acid metabolism proteins on Mouse Genome

IPI Record Position
1: Alox12 11:70057650-70071536
2: Alox12b 11:68973267-68985986
3: Alox12e 11:70131808-70138713
4: Alox15 11:70160347-70168210
5: Alox8 11:69000080-69014034
6: Cbr1 16:93496379-93498862
7: Cbr2 11:120545581-120548081
8: Cbr3 16:93571755-93579526
9: Cyp2b10 7:25606418-25635383
10: Cyp2b13 7:25770255-25804956
11: Cyp2b19 7:26465947-26481390
12: Cyp2b9 7:25882169-25919420
13: Cyp2c29 19:39340422-39384010
14: Cyp2c37 19:40045735-40065554
15: Cyp2c38 19:39442867-39516386
16: Cyp2c39 19:39564182-39621840
17: Cyp2c44 19:44058333-44082510
18: Cyp2c50 19:40142995-40167261
19: Cyp2c54 19:40091252-40127122
20: Cyp2c55 19:39072063-39107731
21: Cyp2c65 19:39126059-39158594
22: Cyp2c66 19:39178942-39240067
23: Cyp2c70 19:40206887-40240597
24: Cyp2e1 7:140615152-140626301
25: Cyp2j5 4:96120789-96156095
26: Cyp2j6 4:96009175-96045679
27: Cyp2j9 4:96060447-96083503
28: Cyp2u1 3:131284541-131292282
29: Cyp4a10 4:115016219-115031581
30: Cyp4a12b 4:114796978-114936971
31: Cyp4a14 4:114984077-114994064
32: Cyp4f13 17:32663087-32685779
33: Cyp4f14 17:32643491-32655747
34: Cyp4f15 17:32424969-32442659
35: Cyp4f18 8:74917471-74938617
36: Dhrs4 14:54432868-54444411
37: Ephx2 14:65038487-65078610
38: Ggt1 10:75012380-75029906
39: Ggtl3 2:155181828-155206284
40: Ggtla1 10:75033097-75060916
41: Gpx1 9:108197405-108198228
42: Gpx2 12:77711490-77714215
43: Gpx3 11:54746389-54753081
44: Gpx5 13:21293898-21300151
45: Gpx6 13:21319715-21327085
46: Gpx7 4:107898322-107904646
47: Lta4h 10:92883228-92914653
48: Ltc4s 11:50079885-50081955
49: Pla2g10 16:13628640-13644163
50: Pla2g12a 3:129870628-129887841
51: Pla2g12b 10:58799042-58817347
52: Pla2g1b 5:115727265-115735716
53: Pla2g2a 4:138103952-138107263
54: Pla2g2c 4:137997804-138016649
55: Pla2g2d 4:138047811-138054219
56: Pla2g2e 4:138150018-138154895
57: Pla2g2f 4:138150018-138154895
58: Pla2g4a 1:151591836-151723502
59: Pla2g4e 2:119857853-119936776
60: Pla2g5 4:138071320-138135558
61: Pla2g6 15:79113485-79155439
62: Ptgds 2:25286029-25291745
63: Ptges 2:30711480-30725306
64: Ptges2 2:32218267-32224748
65: Ptgis 2:166883022-166931749
66: Ptgs1 2:36052509-36074278
67: Ptgs2 1:151862342-151870203
68: Tbxas1 6:38848593-39014194

Human

There are 53 IPI Records from this pathway found in Homo sapiens.

Location of Arachidonic acid metabolism proteins on Human Genome

IPI Record Position
1: AKR1C3 10:5125985-5139878
2: ALOX12 17:6840108-6856220
3: ALOX12B 17:7916679-7931747
4: ALOX15 17:4480963-4491709
5: ALOX15B 17:7883086-7893177
6: ALOX5 10:45189635-45261567
7: CBR1 21:36364155-36367332
8: CBR3 21:36429080-36440722
9: CYP2B6 19:46189044-46216141
10: CYP2C18 10:96433368-96485937
11: CYP2C19 10:96512371-96603007
12: CYP2C8 10:96786520-96819244
13: CYP2C9 10:96688418-96739137
14: CYP2E1 10:135190857-135224714
15: CYP2J2 1:60131568-60165050
16: CYP2U1 4:109072166-109094060
17: CYP4A11 1:47167493-47180004
18: CYP4A22 1:47375433-47387940
19: CYP4F2 19:15849834-15869885
20: CYP4F3 19:15613196-15631581
21: DHRS4 14:23492805-23508326
22: EPHX2 8:27404543-27458403
23: GGT1 22:23309718-23354972
24: GGTL3 20:32896184-32924318
25: GGTL4 22:21316946-21320377
26: GPX1 3:49369616-49371037
27: GPX2 14:64475625-64479284
28: GPX3 5:150380112-150388741
29: GPX4 19:1054936-1057776
30: GPX5 6:28601681-28610706
31: GPX6 6:28579052-28591549
32: GPX7 1:52840632-52847311
33: LTA4H 12:94918742-94953496
34: LTC4S 5:179092457-179156119
35: PGDS 4:95438730-95483050
36: PLA2G10 16:14673908-14696027
37: PLA2G12A 4:110854140-110870660
38: PLA2G12B 10:74364934-74384542
39: PLA2G1B 12:119244298-119249975
40: PLA2G2A 1:20174518-20179496
41: PLA2G2D 1:20311019-20318637
42: PLA2G2E 1:20119089-20122697
43: PLA2G2F 1:20338406-20349466
44: PLA2G3 22:29860795-29866593
45: PLA2G4A 1:185064708-185224736
46: PLA2G5 1:20269288-20290248
47: PLA2G6 22:36837449-36907763
48: PTGDS 9:138989367-139000031
49: PTGES 9:131540433-131555165
50: PTGES2 9:129922793-129930562
51: PTGIS 20:47553818-47618114
52: PTGS1 9:124173050-124197802
53: PTGS2 1:184907546-184916178
54: TBXAS1 7:139124668-139366560

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Recent Literature

Linoleic acid is associated with lower long-chain n-6 and n-3 fatty acids in red blood cell lipids of Canadian pregnant women.

Am J Clin Nutr. 2009 Nov 18;
Friesen RW, Innis SM

BACKGROUND: Arachidonic (ARA), eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids are important in membrane glycerophospholipids. Higher maternal blood ARA, EPA, and DHA concentrations in gestation are associated with higher maternal-to-fetal transfer of ARA, EPA, and DHA, respectively, which emphasizes the importance of maternal fatty acid status in gestation. As in the brain, red blood cell (RBC) ethanolamine phosphoglycerides (EPGs) are high in plasmalogen, ARA, and DHA. OBJECTIVE: We determined the relation between dietary n-6 (omega-6) and n-3 (omega-3) fatty acid intakes and n-6 and n-3 fatty acids in RBC EPGs and phosphatidylcholine in near-term pregnant women. DESIGN: The subjects were 105 healthy Canadian pregnant (36 wk gestation) women. Fatty acid intakes were estimated by food-frequency questionnaire, and fasting venous blood samples were collected. RESULTS: DHA and EPA intakes were positively associated with RBC EPG and phosphatidylcholine concentrations of DHA (rho = 0.309 and 0.369, respectively; P < 0.001) and EPA (rho = 0.391 and 0.228, respectively; P < 0.001) and inversely associated with RBC EPG 22:4n-6 and 22:5n-6 (P < 0.001). In RBCs, concentrations of linoleic acid (LA, 18:2n-6) were inversely associated with DHA, EPA, and ARA, respectively, in EPGs (r = -0.432, P < 0.01; r = -0.201, P < 0.04; and r = -0.303, P < 0.01) and phosphatidylcholine (r = -0.460, -0.490, and -0.604; P < 0.01 for all). CONCLUSIONS: Membrane fatty acids are influenced by the amount and balance of fatty acid substrates. Our results suggest the competitive interaction of LA with ARA, EPA, and DHA, with no evidence that higher LA increases ARA. Biochemical indicators to suggest that DHA is limiting are present in our population. This trial was registered at clinicaltrials.gov as NCT00620672.

Pachymic acid inhibits cell growth and modulates Arachidonic acid metabolism in nonsmall cell lung cancer A549 cells.

Mol Carcinog. 2009 Nov 13;
Ling H, Jia X, Zhang Y, Gapter LA, Lim YS, Agarwal R, Ng KY

Aberrant Arachidonic acid (AA) metabolism has been involved in inflammation and carcinogenesis. The key enzymes in AA metabolism such as cytosolic phospholipase A2 (cPLA(2)) and cyclooxygenase-2 (COX-2) have been implicated in the development and progression of many human cancers, including lung cancer. Hence, the blockade of these enzymes may suppress promotion and survival of human cancer cells. We and others have shown that a natural triterpenoid, pachymic acid (PA), can exhibit antiinflammatory and anticancer properties; however, its potential mechanism has not been fully clarified. In this study, we examined the effect of PA on the proliferation of human nonsmall cell lung cancer A549 cells. Furthermore, we investigated the influences of nontoxic levels of PA on AA metabolism. Additionally, the cellular events and signal transduction pathways influenced by PA were also examined. Our results showed that PA (1) inhibited anchorage-dependent and -independent A549 growth in a concentration-dependent manner, (2) induced apoptosis and disrupted mitochondrial membrane potential in A549 cells, and at nonlethal levels, (3) decreased IL-1beta-induced activation of cPLA(2) and COX-2, (4) suppressed IL-1beta-induced activation of mitogen-activated protein kinases (MAPKs), and (5) inhibited IL-1beta-stimulated nuclear factor kappa B (NF-kappaB) signaling pathways. We speculate that inhibition of AA metabolism by PA is mediated in part by its inhibition of MAPKs and NF-kappaB signaling pathways. Our study reveals that, apart from its cytotoxic effect, PA has the chemopreventive potential by reducing production of eicosanoids from AA metabolism. (c) 2009 Wiley-Liss, Inc.

Distribution of omega-3 fatty acids in tissues of rabbits fed a flaxseed-supplemented diet.

metabolism. 2009 Nov 13;
Ander BP, Edel AL, McCullough R, Rodriguez-Leyva D, Rampersad P, Gilchrist JS, Lukas A, Pierce GN

Diets rich in omega-3 polyunsaturated fatty acids are associated with decreased incidences of cardiovascular disease. The extent of incorporation and distribution of these beneficial fats into body tissues is uncertain. Rabbits were fed regular rabbit chow or a diet containing 10% ground flaxseed that is highly enriched with the omega-3 polyunsaturated fatty acid alpha-linolenic acid (ALA). The high-flaxseed diet resulted in an incorporation of ALA in all tissues, but mostly in the heart and liver with little in the brain. Docosahexaenoic and eicosapentaenoic acid levels were also selectively increased in some tissues, and the effects were not as large as ALA. Arachidonic acid and the ratio of omega-6/omega-3 fatty acids were decreased in all tissues obtained from the flax-supplemented group. Consumption of dietary flaxseed appears to be an effective means to increase ALA content in body tissues, but the degree will depend upon the tissues examined.

Analysis of transcriptome and metabolome profiles alterations in fatty liver induced by high-fat diet in rat.

metabolism. 2009 Nov 13;
Xie Z, Li H, Wang K, Lin J, Wang Q, Zhao G, Jia W, Zhang Q

Excessive energy intake greatly contributes to the development of nonalcoholic fatty liver disease (NAFLD) in modern society. To better understand the comprehensive mechanisms of NAFLD development, we investigated the metabolic alterations of rats with NAFLD induced by high-fat diet (HFD). Male Wistar rats were fed a HFD or standard chow for control. After 16 weeks, rat serum was collected for biochemical measurement. The rats' livers were resected and subjected to histology inspection and gene expression analysis with complementary DNA microarray and metabolic analysis with gas chromatography-mass spectroscopy. In HFD rats, the serum cholesterol, triglycerides, glucose, and insulin contents were increased; and the total cholesterol and triglycerides in the livers were also significantly increased. Complementary DNA microarray analysis revealed that 130 genes were regulated by HFD. Together with real-time reverse transcriptase polymerase chain reaction, lipid metabolism regulatory members like sterol regulatory element binding factor 1 and stearoyl-coenzyme A desaturase 1 had up-regulation, whereas others like peroxisome proliferator-activated receptor, carnitine palmitoyltransferase 1, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase had repressed expression, in HFD rat livers. Metabolomic analysis showed that tetradecanoic acid, hexadecanoic acid, and oleic acid had elevation and Arachidonic acid and eicosapentaenoic acid had decreased content in HFD rat livers. Amino acids including glycine, alanine, aspartic acid, glutamic acid, and proline contents were decreased. The integrative results from transcriptomic and metabolomic studies revealed that, in HFD rat livers, fatty acid utilization through beta-oxidation was inhibited and lipogenesis was enhanced. These observations facilitated our understanding of the pathways involved in the development of NAFLD induced by HFD.

Increased Bone Mass in Adult Prostacyclin Deficient Mice.

J Endocrinol. 2009 Nov 11;
Nakalekha C, Yokoyama C, Miura H, Alles N, Aoki K, Ohya K, Morita I

Prostaglandins (PGs) are key regulatory factors that affect bone metabolism. Prostaglandin E2 (PGE2) regulates bone resorption and bone formation. Prostacyclin (PGI2) is one of the major products derived from Arachidonic acid by the action of cyclooxygenase and PGI2 synthase (PGIS). Unlike PGE2, there are few reports about the role of PGI2 in bone regulation. Therefore, we investigated the potential effect of PGI2 on bone metabolism. We used PGIS knockout (PGIS-/-), PGIS heterozygous (PGIS+/-) and wild-type mice to investigate the role of PGI2. Notably, PGIS-/- mice gradually displayed an increase in trabecular bone mass in adolescence. Adult PGIS-/- mice showed an increase in trabecular BV/TV. Histomorphometric analysis showed that PGIS-/- mice displayed increases in both bone formation and bone resorption parameters. Levels of serum osteocalcin and C-telopeptides (CTX) were increased in adult PGIS-/- mice. Furthermore, the increased bone mass patterns were rescued in PGIS-/tg mice. In conclusion, adult PGIS-/- mice displayed an overall increase in the levels of both bone formation and bone resorption parameters, which suggests that PGI2 deficiency accelerates high bone turnover activity with a greater increase in bone mass in ageing. These results indicated that PGI2 may contribute to the maintenance of normal bone mass and micro-architecture in mice in age-dependent manner. Our findings demonstrate for the first time that PGI2 is involved in bone metabolism in vivo.

5-Lipoxygenase and Cyclooxygenase-2 in Porcine Parasitic Bronchopneumonia: Immunohistochemical and Biochemical Investigations.

J Comp Pathol. 2009 Nov 9;
Marruchella G, Giacominelli-Stuffler R, Baffoni M, Maccarrone M

Eicosanoids are products of Arachidonic acid metabolism and have numerous biological roles. The present study aimed to investigate the role of 5-lipoxygenase (5-LOX)- and cyclooxygenase-2 (COX-2)- dependent enzymatic pathways in the pathogenesis of porcine parasitic bronchopneumonia caused by Metastrongylus spp. Pulmonary tissue samples from healthy control and parasitized pigs were processed for histopathological, immunohistochemical and biochemical investigations. In control animals, immunohistochemistry demonstrated that 5-LOX and COX-2 expression was almost exclusively limited to the bronchiolar epithelial cells. Parasitized pigs had greater 5-LOX- and COX-2- specific immunoreactivity, involving a wide range of cell types within foci of granulomatous and eosinophilic bronchopneumonia. Biochemical investigations demonstrated the presence of 5-LOX (and the related product Leukotriene B(4)) and COX-2 (and the related product prostaglandin E(2); PGE(2)) in all tissues under study. COX-2 activity and PGE(2) concentration were significantly higher in diseased lungs compared with normal healthy controls. These findings demonstrate that 5-LOX and COX-2 are differentially expressed in normal versus lungworm-infected lungs and therefore suggest that both biochemical pathways are likely to be involved in the pathogenesis of porcine parasitic bronchopneumonia.

Inhibition of soluble epoxide hydrolase enhances the anti-inflammatory effects of aspirin and 5-lipoxygenase activation protein inhibitor in a murine model.

Biochem Pharmacol. 2009 Nov 5;
Liu JY, Yang J, Inceoglu B, Qiu H, Ulu A, Hwang SH, Chiamvimonvat N, Hammock BD

Inflammation is a multi-staged process whose expansive phase is thought to be driven by acutely released Arachidonic acid (AA) and its metabolites. Inhibition of cyclooxygenase (COX), lipoxygenase (LOX), or soluble epoxide hydrolase (sEH) is known to be anti-inflammatory. Inhibition of sEH stabilizes the cytochrome P450 (CYP450) products epoxyeicosatrienoic acids (EETs). Here we used a non-selective COX inhibitor aspirin, a 5-lipoxygenase activation protein (FLAP) inhibitor MK886, and a sEH inhibitor t-AUCB to selectively modulate the branches of AA metabolism in a lipopolysaccharide (LPS)-challenged murine model. We used metabolomic profiling to simultaneously monitor representative AA metabolites of each branch. In addition to the significant crosstalk among branches of the AA cascade during selective modulation of COX, LOX, or sEH, we demonstrated that co-administration of t-AUCB enhanced the anti-inflammatory effects of aspirin or MK886, which was evidenced by the observations that co-administration resulted in favorable eicosanoid profiles and better control of LPS-mediated hypotension as well as hepatic protein expression of COX-2 and 5-LOX. Targeted disruption of the sEH gene displayed a parallel profile to that produced by t-AUCB. These observations demonstrate a significant level of crosstalk among the three major branches of the AA cascade and that they are not simply parallel pathways. These data illustrate that inhibition of sEH by both pharmacological intervention and gene knockout enhances the anti-inflammatory effects of aspirin and MK886, suggesting the possibility of modulating multiple branches to achieve better therapeutic effects.

[Study of metabonomics on pharmacological action appraisal Rhizoma coptidis in rats]

Zhongguo Zhong Yao Za Zhi. 2009 Jul; 34(14): 1845-7
Xu G, Ma X, Zhang Q, Li B, Huang L, Yu R, Liu H

OBJECTIVE: HPLC-MS/MS-based metabonomics method was used to find the possible biomarker of Rhizoma Coptidis in rat urine. METHOD: Sprague-Dawley rats were successively administrated 7 g x kg(-1) aqueous extract of Rhizoma Coptidis for 30 days, urine were collected by metabolism cages and detected by using the HPLC-MS-MS. All dates were analyzed by the principal component analysis (PCA) through using the SIMCA-P 10.0 software. RESULT: The PCA demonstrated that the metabolome between treated group and control group had difference in rat urine sample after of 22 days administrated, for treated group 169 kinds of biomarkers were found including oxalacetic acid, malic acid, 2-ketoglutaric acid, NE, Arachidonic acid, 5-HIAA and other compounds, the result was consistent with pharmacological effects of R. coptidis, such as antiinflammatory, inhibiting biosynthesis of CA biosynthesis, anticentral nerve and energy metabolism inhibition. CONCLUSION: Metabonomics may be available in pharmacological action evaluation of drugs.

Potential mechanisms involved in the prevention of neurodegenerative diseases by lithium.

CNS Neurosci Ther. 2009; 15(4): 333-44
Camins A, Verdaguer E, Junyent F, Yeste-Velasco M, Pelegrí C, Vilaplana J, Pallás M

Lithium is a monovalent cation that was introduced in 1949 by John Cade for the treatment of bipolar disorder. Clinical reports and subsequent studies confirmed this application and the beneficial effects of this compound. However, over the last 15 years, various authors have also demonstrated the neuroprotective effects of lithium against several neurotoxic paradigms. Thus, experimental studies in neuronal cell cultures and animal models of Alzheimer disease and others pathologies have provided strong evidence for the potential benefits of lithium. The main mechanism underlying its neuroprotective effects is thought to be inhibition of glycogen synthase kinase-3 (GSK-3), although other biochemical pathways in the brain could also be affected. In this review, the main mechanisms of lithium action are summarized, including the modulation of glutamate receptors, effects on Arachidonic acid metabolism, its role with respect to AKT, and other potential mechanisms. In addition, its effects on neuroprotective proteins such as Bcl-2 and p53 are also discussed. Although the cellular and molecular biological effects of lithium may constitute an effective therapeutic strategy for Alzheimer disease, further clinical and experimental studies with this drug and specific GSK-3 inhibitors are necessary to confirm the use of lithium in therapeutic approaches to neurodegenerative diseases.

3-Methylcholanthrene and benzo(a)pyrene modulate cardiac cytochrome P450 gene expression and Arachidonic acid metabolism in male Sprague Dawley rats.

Br J Pharmacol. 2009 Nov 4;
Aboutabl ME, Zordoky BN, El-Kadi AO

Background and purpose: There is a strong correlation between cytochrome P450 (P450)-dependent Arachidonic acid metabolism and the pathogenesis of cardiac hypertrophy. Several aryl hydrocarbon receptor (AhR) ligands were found to alter P450-dependent Arachidonic acid metabolism. Here, we have investigated the effect of 3-methylcholanthrene (3-MC) and benzo(a)pyrene (BaP), two AhR ligands, on the development of cardiac hypertrophy. Experimental approach: Male Sprague Dawley rats were injected (i.p.) daily with either 3-MC (10 mg.kg(-1)) or BaP (20 mg.kg(-1)) for 7 days. Then hearts were removed, and the heart to body weight ratio and the gene expression of the hypertrophic markers and P450 genes were determined. Levels of Arachidonic acid metabolites were determined by liquid chromatography-electron spray ionization-mass spectrometry. Key results: Both 3-MC and BaP increased the heart to body weight ratio as well as the hypertrophic markers, atrial natriuretic peptide and brain natriuretic peptide. 3-MC and BaP treatment increased the gene expression of CYP1A1, CYP1B1, CYP2E1, CYP4F4, CYP4F5 and soluble epoxide hydrolase. Both 3-MC and BaP treatments increased the dihydroxyeicosatrienoic acids (DHETs) : epoxyeicosatrienoic acids (EETs) ratio and the 20-hydroxyeicosatetraenoic acid (20-HETE) : total EETs ratio. Treatment with benzo(e)pyrene, an isomer of BaP that is a poor ligand for the AhR, did not induce cardiac hypertrophy in rats, confirming the role of AhR in the development of cardiac hypertrophy. Treatment with the omega-hydroxylase inhibitor, HET0016, significantly reversed BaP-induced cardiac hypertrophy. Conclusions and implications: 3-MC and BaP induce cardiac hypertrophy by increasing the ratio of DHETs : EETs and/or the ratio of 20-HETE : total EETs, through increasing soluble epoxide hydrolase activity.

Long-chain polyunsaturated fatty acids stimulate cellular fatty acid uptake in human placental choriocarcinoma (BeWo) cells.

Placenta. 2009 Oct 30;
Johnsen GM, Weedon-Fekjær MS, Tobin KA, Staff AC, Duttaroy AK

Supplementation of long-chain polyunsaturated fatty acids (LCPUFAs) is advocated during pregnancy in some countries although very little information is available on their effects on placental ability to take up these fatty acids for fetal supply to which the fetal growth and development are critically dependent. To identify the roles of LCPUFAs on placental fatty acid transport function, we examined the effects of LCPUFAs on the uptake of fatty acids and expression of fatty acid transport/metabolic genes using placental trophoblast cells (BeWo). Following 24 h incubation of these cells with 100 muM of LCPUFAs (Arachidonic acid, 20:4n-6, eicosapentaenoic acid, 20:5n-3, or docosahexaenoic acid, 22:6n-3), the cellular uptake of [(14)C] fatty acids was increased by 20-50%, and accumulated fatty acids were preferentially incorporated into phospholipid fractions. Oleic acid (OA, 18:1n-9), on the other hand, could not stimulate fatty acid uptake. LCPUFAs and OA increased the gene expression of ADRP whilst decreased the expression of ASCL3, ACSL4, ACSL6, LPIN1, and FABP3 in these cells. However, LCPUFAs but not OA increased expression of ACSL1 and ACSL5. Since acyl-CoA synthetases are involved in cellular uptake of fatty acids via activation for their channelling to lipid metabolism and/or for storage, the increased expression of ACSL1 and ACLS5 by LCPUFAs may be responsible for the increased fatty acid uptake. These findings demonstrate that LCPUFA may function as an important regulator of general fatty acid uptake in trophoblast cells and may thus have impact on fetal growth and development.

The function of very long chain polyunsaturated fatty acids in the pineal gland.

Biochim Biophys Acta. 2009 Oct 30;
Catalá A

The mammalian pineal gland is a prominent secretory organ with a high metabolic activity. Melatonin (N-acetyl-5-methoxytryptamine), the main secretory product of the pineal gland, efficiently scavenges both the hydroxyl and peroxyl radicals counteracting lipid peroxidation in biological membranes. Approximately 25% of the total fatty acids present in the rat pineal lipids are represented by Arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3). These very long chain polyunsaturated fatty acids play important roles in the pineal gland. In addition to the production of melatonin, the mammalian pineal gland is able of convert these polyunsaturated fatty acids into bioactive lipid mediators. Lipoxygenation is the principal lipoxygenase (LOX) activity observed in the rat pineal gland. Lipoxygenation in the pineal gland is exceptional because no other brain regions express significant LOX activities under normal physiological conditions. The rat pineal gland expresses both 12- and 15-lipoxygenase (LOX) activities, producing 12- and 15-hydroperoxyeicosatetraenoic acid (12- and 15-HpETE) from Arachidonic acid and 14- and 17-hydroxydocosahexaenoic acid (14- and 17-HdoHE) from docosahexaenoic acid, respectively. The rat pineal also produces hepoxilins via LOX pathways. The hepoxilins are bioactive epoxy-hydroxy products of the Arachidonic acid metabolism via the 12S-lipoxygenase (12S-LOX) pathway. The two key pineal biochemical functions, lipoxygenation and melatonin synthesis, may be synergistically regulated by the status of n-3 essential fatty acids.

Dietary Arachidonic acid to EPA and DHA Balance Is Increased among Canadian Pregnant Women with Low Fish Intake.

J Nutr. 2009 Oct 28;
Friesen RW, Innis SM

Arachidonic [ARA, 20:4(n-6)], eicosapentaenoic [EPA, 20:5(n-3)], and docosahexaenoic acids [DHA, 22:6(n-3)] occur in the diet in animal tissue lipids, play important roles in human development and health, but have interactive and opposing functions. Meat and poultry have higher ARA and fish are richer in EPA and DHA. National databases were recently revised to include complete data on ARA in foods. We used a validated FFQ and the revised nutrient databases to quantify the distribution of ARA, EPA, and DHA intakes and balance for 204 healthy Canadian pregnant women. We focused on intake distributions because risk of adverse health effects increases at lower nutrient intakes. RBC fatty acids were analyzed concurrent with dietary assessment. The distribution of ARA, EPA, and DHA intakes were skewed (P < 0.001), with a median (5-95th percentile) of 107 (41-225), 65 (10-228), and 105 (10-430) mg/d ARA, EPA, and DHA, respectively. Fish provided 66 and 76% of EPA and DHA, respectively, whereas eggs, poultry, and meats provided 81% of ARA. Women consuming <101 g fish/wk consumed less EPA and DHA and had markedly elevated median dietary ARA:EPA and ARA:DHA ratios and RBC lipid ARA:EPA + DHA ratios compared with women consuming >/=101 g fish/wk (P < 0.001). Relatively small increases in fish intake of 1-2 servings (25-50 g)/wk corrected the distorted dietary (n-6):(n-3) fatty acid balance among women consuming meats, but not fish. Median fish and DHA intakes below the recommended 1-2 servings/wk fish for pregnant women suggest major changes in the availability, cost, or acceptance of fish are needed.

Endocannabinoid-dependent homeostatic regulation of inhibitory synapses by miniature excitatory synaptic activities.

J Neurosci. 2009 Oct 21; 29(42): 13222-31
Zhang SY, Xu M, Miao QL, Poo MM, Zhang XH

Homeostatic regulation of synaptic strength in response to persistent changes of neuronal activity plays an important role in maintaining the overall level of circuit activity within a normal range. Absence of miniature EPSCs (mEPSCs) for a few hours is known to cause upregulation of excitatory synaptic strength, suggesting that mEPSCs contribute to the maintenance of excitatory synaptic functions. In the present study, we found that the absence of mEPSCs for 1-3 h also resulted in homeostatic suppression of presynaptic functions of inhibitory synapses in acute cortical slices from juvenile rats, as suggested by the reduced frequency (but not amplitude) of miniature IPSCs (mIPSCs) as well as the reduced amplitude of IPSCs. This homeostatic regulation depended on endocannabinoid (eCB) signaling, because blockade of either the activation of cannabinoid type-1 receptors (CB1Rs) or the synthesis of its endogenous ligand 2-arachidonoylglycerol (2-AG) abolished the suppression of inhibitory synapses caused by the absence of mEPSCs. Blockade of group I metabotropic glutamate receptors (mGluR-I) also abolished the suppression of inhibitory synapses, consistent with the mGluR-I requirement for eCB synthesis and release in cortical synapses. Furthermore, this homeostatic regulation also required eukaryotic elongation factor-2 (eEF2)-dependent protein synthesis, but not gene transcription. Activation of eEF2 alone was sufficient to suppress the mIPSC frequency, an effect abolished by inhibiting CB1Rs. Thus, mEPSCs contribute to the maintenance of inhibitory synaptic function and the absence of mEPSCs results in presynaptic suppression of inhibitory synapses via protein synthesis-dependent elevation of eCB signaling.

T-type calcium channel inhibition underlies the analgesic effects of the endogenous lipoamino acids.

J Neurosci. 2009 Oct 21; 29(42): 13106-14
Barbara G, Alloui A, Nargeot J, Lory P, Eschalier A, Bourinet E, Chemin J

Lipoamino acids are anandamide-related endogenous molecules that induce analgesia via unresolved mechanisms. Here, we provide evidence that the T-type/Cav3 calcium channels are important pharmacological targets underlying their physiological effects. Various lipoamino acids, including N-arachidonoyl glycine (NAGly), reversibly inhibited Cav3.1, Cav3.2, and Cav3.3 currents, with potent effects on Cav3.2 [EC(50) approximately 200 nm for N-arachidonoyl 3-OH-gamma-aminobutyric acid (NAGABA-OH)]. This inhibition involved a large shift in the Cav3.2 steady-state inactivation and persisted during fatty acid amide hydrolase (FAAH) inhibition as well as in cell-free outside-out patch. In contrast, lipoamino acids had weak effects on high-voltage-activated (HVA) Cav1.2 and Cav2.2 calcium currents, on Nav1.7 and Nav1.8 sodium currents, and on anandamide-sensitive TRPV1 and TASK1 currents. Accordingly, lipoamino acids strongly inhibited native Cav3.2 currents in sensory neurons with small effects on sodium and HVA calcium currents. In addition, we demonstrate here that lipoamino acids NAGly and NAGABA-OH produced a strong thermal analgesia and that these effects (but not those of morphine) were abolished in Cav3.2 knock-out mice. Collectively, our data revealed lipoamino acids as a family of endogenous T-type channel inhibitors, suggesting that these ligands can modulate multiple cell functions via this newly evidenced regulation.

Metabolic profiling reveals key metabolic features of renal cell carcinoma.

J Cell Mol Med. 2009 Oct 20;
Catchpole G, Platzer A, Weikert C, Kempkensteffen C, Johannsen M, Krause H, Jung K, Miller K, Willmitzer L, Selbig J, Weikert S

Abstract Recent evidence suggests that metabolic changes play a pivotal role in the biology of cancer and in particular renal cell carcinoma (RCC). Here, a global metabolite profiling approach was applied to characterize the metabolite pool of RCC and normal renal tissue. Advanced decision tree models were applied to characterize the metabolic signature of RCC and to explore features of metastasized tumors. The findings were validated in a second independent dataset. Vitamin E derivates and metabolites of glucose, fatty acid, and inositol phosphate metabolism determined the metabolic profile of RCC. Alpha-tocopherol, hippuric acid, myoinositol, fructose-1-phosphate, and glucose-1-phosphate contributed most to the tumor/normal discrimination and all showed pronounced concentration changes in RCC. The identified metabolic profile was characterized by a low recognition error of only 5% for tumor versus normal samples. Data on metastasized tumors suggested a key role for metabolic pathways involving Arachidonic acid, free fatty acids, proline, uracil, and the tricarboxylic acid cycle. These results illustrate the potential of mass spectroscopy based metabolomics in conjunction with sophisticated data analysis methods to uncover the metabolic phenotype of cancer. Differentially regulated metabolites, such as vitamin E compounds, hippuric acid, and myoinositol, provide leads for the characterization of novel pathways in RCC.

Gamma tocopherol upregulates the expression of 15-S-HETE and induces growth arrest through a PPAR gamma-dependent mechanism in PC-3 human prostate cancer cells.

Nutr Cancer. 2009; 61(5): 649-62
Campbell SE, Musich PR, Whaley SG, Stimmel JB, Leesnitzer LM, Dessus-Babus S, Duffourc M, Stone W, Newman RA, Yang P, Krishnan K

Chronic inflammation and dietary fat consumption correlates with an increase in prostate cancer. Our previous studies in the colon have demonstrated that gamma-tocopherol treatment could upregulate the expression of peroxisome proliferator-activated preceptors (PPAR) gamma, a nuclear receptor involved in fatty acid metabolism as well modulation of cell proliferation and differentiation. In this study, we explored the possibility that gamma-tocopherol could induce growth arrest in PC-3 prostate cancer cells through the regulation of fatty acid metabolism. Growth arrest (40%) and PPAR gamma mRNA and protein upregulation was achieved with gamma-tocopherol within 6 h. gamma-Tocopherol-mediated growth arrest was demonstrated to be PPAR gamma dependent using the agonist GW9662 and a PPAR gamma dominant negative vector. gamma-tocopherol was shown not to be a direct PPAR gamma ligand, but rather 15-S-HETE (an endogenous PPAR gamma ligand) was upregulated by gamma-tocopherol treatment. 15-Lipoxygenase-2, a tumor suppressor and the enzyme that converts Arachidonic acid to 15-S-HETE, was upregulated at 3 h following gamma-tocopherol treatment. Expression of proteins downstream of the PPAR gamma pathway were examined. Cyclin D1, cyclin D3, bcl-2, and NFkappa B proteins were found to be downregulated following gamma-tocopherol treatment. These data demonstrate that the growth arrest mediated by gamma-tocopherol follows a PPAR-gamma-dependent mechanism.

Arachidonic and docosahexaenoic acid deficits in preterm neonatal mononuclear cell membranes. Implications for the immune response at birth.

Nutr Health. 2009; 20(2): 167-85
Moodley T, Vella C, Djahanbakhch O, Branford-White CJ, Crawford MA

Preterm neonates are more susceptible to infection than term neonates. Arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3) are biologically active components of cell membrane phospholipids. Arachidonic acid is a substrate for the synthesis of eicosanoids, potent regulators of immune function. Preterm babies may have a deficiency of Arachidonic acid and docosahexaenoic acid, but the impact of this deficit on maturation of the immune system is unknown. To address this we explored links between placental provision of fatty acids to cord blood mononuclear cell (CBMC) membranes using gas chromatography (GC), and maturation of the immune response with gestational age by analysing lymphocyte subsets by flow cytometry. This is the first study to examine the lipid profile of the phosphatidylcholine (PC) and phosphatidylethanolamine (PE) fractions of CBMC membranes from preterm neonates. The long chain polyunsaturated fatty acid (LCPUFA) composition of CBMC membranes was dominated by Arachidonic acid in both PE (34%) and PC (15%) fractions in healthy term neonates (> or =37 weeks, n=9), whilst in healthy preterm neonates (<37 weeks, n=10) the level of Arachidonic acid was significantly lower at 28.8% and 12.5% respectively (p<0.05). Preterm neonates (<37 weeks, n=23) also had significantly lower absolute numbers of CD4+ (p<0.05) leukocytes and CD4+ (p<0.01) and CD8+ (p<0.05) naïve T-cells than term (> or =37 weeks, n=24) neonates that correlated with gestational age (p<0.01-0.05).

Increased Tissue Arachidonic acid and Reduced Linoleic acid in a Mouse Model of Cystic Fibrosis Are Reversed by Supplemental Glycerophospholipids Enriched in Docosahexaenoic acid.

J Nutr. 2009 Oct 14;
Mimoun M, Coste TC, Lebacq J, Lebecque P, Wallemacq P, Leal T, Armand M

An imbalance in (n-6)/(n-3) PUFA has been reported in cystic fibrosis (CF) patients. Glycerophospholipids enriched in docosahexaenoic acid (GPL-DHA) have been shown to regulate the (n-6)/(n-3) fatty acid ratio in the elderly. Here, we tested the effect of GPL-DHA supplementation on PUFA status in F508del homozygous CF mice. GPL-DHA liposomes were administrated by gavage (60 mg DHA/kg daily, i.e. at maximum 1.4 mg DHA/d) to 1.5-mo-old CF mice (CF+DHA) and their corresponding wild-type (WT) homozygous littermates (WT+DHA) for 6 wk. The PUFA status of different tissues was determined by GC and compared with control groups (CF and WT). There was an alteration in the (n-6) PUFA pathway in several CF-target organs in CF compared with WT mice, as evidenced by a higher level of Arachidonic acid (AA) in membrane phospholipids or whole tissue (21 and 39% in duodenum-jejunum, 32 and 38% in ileum, and 19 and 43% in pancreas). Elevated AA levels were associated with lower linoleic acid (LA) and higher dihomo-gamma-linolenic acid levels. No DHA deficiency was observed. GPL-DHA treatment resulted in different PUFA composition changes depending on the tissue (increase in LA, decrease in elevated AA, DHA increase, increase in (n-6)/(n-3) fatty acid ratio). However, the DHA/AA ratio consistently increased in all tissues in CF+DHA and WT+DHA mice. Our study demonstrates the effectiveness of an original oral DHA formulation in counter-balancing the abnormal (n-6) fatty acid metabolism in organs of CF mice when administrated at a low dose and highlights the potential of the use of GPL-DHA as nutritherapy for CF patients.

Enhanced lumbar spine bone mineral content in piglets fed Arachidonic acid and docosahexaenoic acid is modulated by severity of growth restriction.

Br J Nutr. 2009 Oct; 102(8): 1117-20
Kohut J, Watkins B, Weiler H

The infant born small size for gestational age (SGA) has low bone mass. Since dietary Arachidonic acid (AA) and DHA enhance bone mass in normal-birth-weight piglets the objective of the present study was to test for such benefits in the SGA piglet. In the present 15 d study, two levels of dietary AA and DHA (6:1 ratio of AA:DHA diets, 0.6:0.1 or 1.2:0.2 g/100 g dietary fat) v. a control diet were tested for effects on growth, fatty acid status, whole-body and regional bone mineral content (BMC) and metabolism in SGA piglets categorised as either very low birth weight (VLBW; < or = 1.0 kg; n 12) or low birth weight (LBW; 1.1 to 1.2 kg; n 18). Differences in outcomes for each body weight category were detected using ANOVA with post hoc Bonferroni tests. Growth was not influenced by diet, yet the LBW piglets fed 0.6:0.1 AA and DHA as g/100 g fat had elevated BMC in the spine, whereas the VLBW piglets had higher BMC of the spine if fed the higher intake of AA and DHA. In both weight categories, the higher intake of AA and DHA lowered bone resorption relative to controls, whereas bone formation was unchanged. Tissue fatty acid concentrations reflected dietary AA and DHA, especially trabecular bone of VLBW piglets. Whether the enhanced lumbar spine BMC is due to enhanced Ca absorption and thus suppression of bone resorption remains to be established.