NUTRITIONAL STUDIES WITH THE GUINEA PIG. X. DETERMINATION OF THE LINOLEIC ACID REQUIREMENT.
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Chromatography↗
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High dietary linoleic acid content modulates neutrophil function in rats.
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Animals↗
Metabolism of oxidized linoleic acid by glutathione transferases: peroxidase activity toward 13-hydroperoxyoctadecadienoic acid.
The oxidation of linoleic acid produces several products with biological activity including the hydroperoxy fatty acid 13-hydroperoxyoctadecadienoic acid (13-HPODE), the hydroxy fatty acid 13-hydroxyoctadecadienoic acid (13-HODE), and the 2,4-dienone 13-oxooctadecadienoic acid (13-OXO). In the present work, the peroxidase activity of glutathione transferases (GST) A1-1, M1-1, M2-2, and P1-1(Val 105) toward 13-HPODE has been examined. The alpha class enzyme is the most efficient peroxidase while the two enzymes from the mu class exhibit weak peroxidase activity toward 13-HPODE. It was also determined that the conjugated diene 13-HODE is not a substrate for GST from the alpha and mu classes but that 13-HODE does inhibit the GST-catalyzed conjugation of CDNB by enzymes from the alpha, mu, and pi classes. Finally, both 13-HODE and 13-OXO were shown to be inducers of GST activity in HT-29 and HCT-116 colon tumor cells. These data help to clarify the role of GST in the metabolic disposition of linoleic acid oxidation products.
Acetonitriles↗
Rat testis lipoxygenase-like enzyme. Characterization of products from linoleic acid.
The linoleate oxidation products of the affinity chromatography-purified lipoxygenase-like enzyme isolated from rat testes microsomes were characterized. Three types of reaction products separated by thin-layer chromatography were generally present: polar byproducts (A and B) and hydroperoxides. The methyl hydroxystearates obtained from the enzymically produced hydroperoxides were analysed by gas-liquid chromatography and showed a ratio of 67% 13-hydroxy isomer to 33% 9-hydroxy isomer. The major polar byproduct was analysed by infrared spectra, nuclear magnetic resonance and mass spectrometry (of the toluene-p-sulphonyl derivative) and its structure was established as 13-hydroxy-12-oxo-octadec-cis-9-enoic acid. The possibility of the existence of a linoleate hydroperoxide isomerase in the affinity-purified preparation is discussed.
Animals↗
[Digestive utilization of cis and trans docosenoic acids in the rat: effects of dietary levels of calcium and linoleic acid].
Digestibilities of cis and trans docosenoic acids (C 22:11) have been determined in male growing Wistar rats. Eight groups of rats were fed diets with 0.04 or 0.92% calcium and 15% lipids; the latter contained about 46% cis or trans C:22:1, and 1.5 or 28% linoleic acid. Food consumption was recorded and faeces were collected during 9 days. Fecal lipids were extracted in two fractions: soluble (in chloroform), and insoluble; the fatty acids of both fractions were analysed by gas-liquid chromatography. Calcium and, in some cases, Phosphorus, were determined in the soluble fraction. The digestibility of brassidic acid was strongly lowered by the presence of Calcium in the diet (-35 points). This was due to the massive formation, in the gut, of insoluble Calcium complexes (probably Calcium soaps) of brassidic acid. Dietary linoleic acid improves the absorption of brassidic acid (+ 17 points). This effect could result from the lower melting point of the dietary fat (37 degrees C instead of 48 degrees C) and/or from the emulsifying properties of monolinolein in the intestine. The effects of Calcium and of linoleic acid were additives. In the most favourable conditions (no Calcium, 28% linoleic acid), brassidic acid digestibility reached 98%. Erucic acid digestibility was decreased by dietary Calcium, but to a lesser extent than that of brassidic acid (-17 points). Here again, the formation in the gut of Calcium erucate and Calcium-Phosphorus-erucate complexes was responsible of this phenomenon. As a matter of fact, the digestibility of erucic acid reached nearly 100% when no Calcium was added to the diet. The absorption of erucic acid was not improved by dietary linoleic acid.
Animals↗
Milk fat synthesis in dairy cows is progressively reduced by increasing supplemental amounts of trans-10, cis-12 conjugated linoleic acid (CLA).
Conjugated linoleic acid (CLA) supplements containing a variety of isomers reduce milk fat yield. We have recently identified trans-10, cis-12 CLA as the isomer responsible for inhibiting milk fat synthesis in dairy cows. Our objectives were to determine milk fat yield and fatty acid composition responses to different doses of trans-10, cis-12 CLA. Multiparous Holstein cows (n = 4) were used in a 4 x 4 Latin square design. Treatments consisted of a 5-d abomasal infusion of four doses of trans-10, cis-12 CLA, i.e., 0.0, 3.5, 7.0 and 14.0 g/d. Milk fat yield was decreased 25, 33, and 50%, and milk fat concentration was reduced 24, 37 and 46% when cows received 3.5, 7.0 and 14.0 g/d of trans-10, cis-12 CLA, respectively. Feed intake, milk yield, and milk protein content and yield were unaffected by treatment. Milk fatty acid composition revealed that de novo synthesized fatty acids (short and medium chain) were extensively reduced when cows received the two highest doses, but at the low dose (3.5 g/d), decreases in de novo synthesized fatty acids and preformed fatty acids were similar. Changes in milk fatty acid composition also demonstrated that (9)-desaturase activity was inhibited at the two high doses of trans-10, cis-12 CLA, but was unaffected by the low dose. Results indicate minimal quantities of trans-10, cis-12 CLA (0.016% of dietary dry matter) markedly inhibited milk fat synthesis (25% reduction) and that a curvilinear reduction in milk fat yield occurred with increasing quantities of trans-10, cis-12 CLA.
Animal Feed↗
Biological activities of conjugated fatty acids: conjugated eicosadienoic (conj. 20:2delta(c11,t13/t12,c14)), eicosatrienoic (conj. 20:3delta(c8,t12,c14)), and heneicosadienoic (conj. 21:2delta(c12,t14/c13,t15)) acids and other metabolites of conjugated linoleic acid.
The elongated form of conjugated linoleic acid (CLA), conjugated eicosadienoic acid (CEA, conj. 20:2delta(c11,t13/t12,c14)), was generated from CLA by liver microsomal fractions. Subsequent testing showed that dietary CEA significantly reduced body fat, and increased lean mass similar to CLA when compared to controls. CEA also decreased lipoprotein lipase activity and triacylglyceride, and increased glycerol release in 3T3-L1 adipocytes, correlated with the trans-12,cis-14 isomer, but CEA required a longer incubation period than cells treated with CLA. Based on the fact that CEA fed animals had CLA in tissue, we suggest that the effect of CEA is due to the CLA converted from CEA in the system. The delta-6 desaturated and elongated form of trans-10,cis-12 CLA (conjugated eicosatrienoic acid, CETA, conj. 20:3delta(c8,t12,c14)) inhibited LPL activity and increased glycerol release but was less active than trans-10,cis-12 CLA or CEA. The 21-carbon conjugated fatty acid, conjugated heneicosadienoic acid (CHDA, conj. 21:2delta(c12,t14/c13,t15)), was not active on LPL inhibition, triacylglyceride, or glycerol release in 3T3-L1 adipocytes. We also provide evidence that CLA was metabolized to conjugated dodecadienoic acid (conj. 12:2delta(c3,t5/t4,c6)). In addition, there were indications of the presence of conjugated tetradecadienoic acid (conj. 14:2delta(c5,t7/t6,c8)), suggesting that CLA can be metabolized through fatty acid beta-oxidation. This is the first work to report the presence of conjugated 12 and 14 carbon fatty acids, originated from CLA, and the biological activities of CEA, CETA and CHDA.
Animals↗
Effects of lipophilic derivatives of L-ascorbic acid and dehydro-L-ascorbic acid on the peroxidation of linoleic acid in neutral phosphate buffer containing alcohol.
6-O-Palmitoyl-AsA (AP) and -DHA (DHAP) suppressed LA peroxidation considerably in both 10% and 20% EtOH solutions. The duration of the suppression of LA peroxidation was longer with AP than with DHAP. But after the initial suppression of LA peroxidation, both derivatives showed an accelerating effect. 6-O-Acetyl-AsA (Ac-AsA) and -DHA (Ac-DHA) accelerated LA peroxidation from the start of the reaction in 10% EtOH, but suppressed it notably in 20% EtOH. 4-Phenyl-2,3-dihydroxy-2-buten-4-olide (PDHB) and 4-phenyl-2,3-dioxo-4-butenolide (PDOB) accelerated LA peroxidation in 10% EtOH. With 20% EtOH solution, PDHB suppressed LA peroxidation notably, as did AP, but PDOB showed only a short duration (about 1 h) of suppression. These results suggest the complexity of LA peroxidation catalyzed by lipophilic AsA or DHA in aqueous solution containing alcohol.
4-Butyrolactone↗
A linoleic acid (8R)-dioxygenase and hydroperoxide isomerase of the fungus Gaeumannomyces graminis. Biosynthesis of (8R)-hydroxylinoleic acid and (7S,8S)-dihydroxylinoleic acid from (8R)-hydroperoxylinoleic acid.
The fungus Gaeumannomyces graminis metabolized linoleic acid extensively to (8R)-hydroperoxylinoleic acid, (8R)-hydroxylinoleic acid, and threo-(7S,8S)-dihydroxylinoleic acid. When G. graminis was incubated with linoleic acid under an atmosphere of oxygen-18, the isotope was incorporated into (8R)-hydroxylinoleic acid and 7,8-dihydroxylinoleic acid. The two hydroxyls of the latter contained either two oxygen-18 or two oxygen-16 atoms, whereas a molecular species that contained both oxygen isotopes was formed in negligible amounts. Glutathione peroxidase inhibited the biosynthesis of 7,8-dihydroxylinoleic acid. These findings demonstrated that the diol was formed from (8R)-hydroperoxylinoleic acid by intramolecular hydroxylation at carbon 7, catalyzed by a hydroperoxide isomerase. The (8R)-dioxygenase appeared to metabolize substrates with a saturated carboxylic side chain and a 9Z-double bond. G. graminis also formed omega 2- and omega 3-hydroxy metabolites of the fatty acids. In addition, linoleic acid was converted to small amounts of nearly (65% R) racemic 10-hydroxy-8,12-octadecadienoic acid by incorporation of atmospheric oxygen. An unstable metabolite, 11-hydroxylinoleic acid, could also be isolated as well as (13R,13S)-hydroxy-(9E,9Z), (11E)-octadecadienoic acids and (9R,9S)-hydroxy-(10E), (12E,12Z)-octadecadienoic acids. In summary, G. graminis contains a prominent linoleic acid (8R)-dioxygenase, which differs from the lipoxygenase family of dioxygenases by catalyzing the formation of a hydroperoxide without affecting the double bonds of the substrate.
Ascomycota↗
The origin and structures of dimeric fatty acids from the anaerobic reaction between soya-bean lipoxygenase, linoleic acid and its hydroperoxide.
In an anaerobic system soya-bean lipoxygenase catalyses in the presence of linoleic acid and l-13-hydroperoxyoctadeca-cis-9-trans-11-dienoic acid the formation of dimeric fatty acids and of carbonyl compounds. The analogous reaction does not take place when d-9-hydroperoxyoctadeca-trans-10-cis-12-dienoic acid is used instead of the 13-hydroperoxy isomer. Non-oxygenated dimers stem directly from linoleic acid and have C((11))-C((13')) or -C((9')) and C((13))-C((13')) or -C((9')) linkages. Dimers that contain oxygen originate from linoleic acid and linoleic acid hydroperoxide. It is most likely that the oxygen is present in epoxy groups.
Anaerobiosis↗
Origin of hepatic triglyceride fatty acids: quantitative estimation of the relative contributions of linoleic acid by diet and adipose tissue in normal and ethanol-fed rats.
The present study demonstrates that the rat liver obtains most of its triglyceride fatty acids from dietary sources. The dietary and adipose tissue contributions of linoleic acid for hepatic triglyceride esterification were shown to be 50.42 and 13.85 micro moles, respectively, during a 4-day period. When ethanol provided 40% of the caloric intake, fatty liver developed and hepatic triglyceride content increased threefold. Under these conditions, the dietary and adipose tissue contributions of linoleic acid were estimated at 192.85 and 10.73 micro moles, respectively. This increase in dietary fatty acid utilization was sufficient to account for the entire increase in esterified hepatic linoleic acid. Any explanation of these observations must include the high dietary fatty acid utilization in both control and ethanol-treated animals. One possibility is that most dietary lipids first enter a rapidly turning over pool in adipose tissue from which most hepatic triglyceride fatty acids are derived. Another is that dietary fatty acids, incorporated into chylomicrons, are stored separately and used preferentially by the liver as compared with lipids derived from adipose tissue and bound to albumin. The pros and cons of these possibilities are discussed.
Adipose Tissue↗
Analysis of the toxic effects of linoleic acid, 12,13-cis-epoxyoctadecenoic acid, and 12,13-dihydroxyoctadecenoic acid in rabbit renal cortical mitochondria.
P450 epoxidation of linoleic acid has been associated with many pathological conditions that often lead to acute renal failure. However, there is only suggestive evidence that linoleic acid monoepoxides and/or linoleic diols directly induce mitochondrial dysfunction. Using isolated rabbit renal cortical mitochondria (RCM), we found that linoleic acid (50 microM) and the linoleic acid monoepoxide, cis-12,13-epoxy-9-octadecenoic acid (12,13-EOA, 50 microM) increased state 4 and oligomycin-insensitive respiration and reduced state 3 and oligomycin-sensitive respiration. Concomitant with these effects, linoleic acid and 12,13-EOA decreased mitochondrial membrane potential (DeltaPsi). In contrast, the hydrolyzed product of 12,13-EOA, 12,13-dihydroxyoctadecenoic acid (12,13-DHOA, 50 microM), had no effect on state 3, state 4, oligomycin-sensitive, and oligomycin-insensitive respiration, and DeltaPsi. Neither linoleic acid or its metabolites altered uncoupled respiration, which suggests that these compounds have no affect on electron transport chain in RCM. Nucleotides such as ATP (0.5 mM) and GDP (0.5 mM) partially prevented the decrease in DeltaPsi but did not attenuate the increase in oligomycin-insensitive respiration after exposure to linoleic acid (50 microM) and 12,13-EOA (50 microM). These results demonstrate that linoleic acid metabolism to the 12,13-DHOA is a detoxification pathway that prevents mitochondrial dysfunction in RCM. The increase in state 4 respiration concomitant with decreases in state 3 respiration and DeltaPsi suggest that, in addition to uncoupling effects, linoleic acid and 12,13-EOA may have other effects, such as alterations of mitochondrial membranes. The inability of ATP and GDP to fully attenuate the uncoupling effects of linoleic acid and 12,13-EOA suggests that these effects are mediated through a nucleotide-independent mechanism.
Adenosine Triphosphate↗
The effect of conjugated linoleic acid isomers on fatty acid profiles of liver and adipose tissues and their conversion to isomers of 16:2 and 18:3 conjugated fatty acids in rats.
Conjugated linoleic acid (CLA) is a collective term that describes different isomers of linoleic acid with conjugated double bonds. Although the main dietary isomer is 9cis,11trans-18:2, which is present in dairy products and ruminant fat, the biological effects of CLA generally have been studied using mixtures in which the 9cis,11trans- and the 10trans,12cis-18:2 were present at similar levels. In the present work, we have studied the impact of each isomer (9cis,11 trans- and 10trans,12cis-18:2) given separately in the diet of rats for 6 wk. The 10trans,12cis-18:2 decreased the triacylglycerol content of the liver (-32%) and increased the 18:0 content at the expense of 18:1 n-9, suggesting an alteration of the delta9 desaturase activity, as was already demonstrated in vitro. This was not observed when the 9cis,11trans-18:2 was given in the diet. Moreover, the 10trans,12cis-18:2 induced an increase in the C22 polyunsaturated fatty acids in the liver lipids. The 10trans,12cis-18:2 was mainly metabolized into conjugated 16:2 and 18:3, which have been identified. The 9cis,11trans isomer was preferentially metabolized into a conjugated 20:3 isomer. Thus, the 9cis,11trans- and the 10trans,12cis-CLA isomers are metabolized differently and have distinct effects on the metabolism of polyunsaturated fatty acids in rat liver while altering liver triglyceride levels differentially.
Adipose Tissue↗
Conjugated linoleic acid and disease prevention: a review of current knowledge.
Conjugated linoleic acid (CLA), a derivative of a fatty acid linoleic acid (LA), has been reported to decrease tumorigenesis in animals. CLA is unique because unlike most antioxidants which are components of plant products, it is present in food from animal sources such as dairy foods and meats. CLA concentrations in dairy products typically range from 2.9 to 8.92 mg/g fat of which the 9-cis, 11-trans isomer makes up to 73% to 93% of the total CLA. Low concentrations of CLA are found in human blood and tissues. In vitro results suggest that CLA is cytotoxic to MCF-7 cells and it inhibits the proliferation of human malignant melanoma and colorectal cancer cells. In animal studies, CLA has inhibited the development of mouse epidermal tumors, mouse forestomach cancer and rat mammary cancer. Hamsters fed CLA collectively had significantly reduced levels of plasma total cholesterol, non-high-density lipoprotein cholesterol, (combined very-low and low-density lipoprotein) and triglycerides with no effect on high-density lipoprotein cholesterol, as compared to controls. Dietary CLA modulated certain aspects of the immune defense but had no obvious effect on the growth of an established, aggressive mammary tumor in mice. It is now thought that CLA itself may not have anti-oxidant capabilities but may produce substances which protect cells from the detrimental effects of peroxides. There is, however, insufficient evidence from human epidemiological data, and very few of the animal studies have shown a dose-response relationship with the quantity of CLA feed and the extent of tumor growth. Further research with tumor models is needed to test the efficacy and utility of CLA in cancer and other disease prevention and form the basis of evaluating its effect in humans by observational studies and clinical trials.
Animals↗
Oxidative stability of conjugated linoleic acid isomers.
Conjugated linoleic acids (CLAs) have been shown to be a strong anticarcinogen in a number of animal models. Our previous study demonstrated that CLA as a whole was extremely unstable in air. The present study was undertaken further to examine the oxidative stability of individual CLA isomers using the combination of gas-liquid chromatography (GLC) and silver ion high-performance liquid chromatography (Ag-HPLC). It was found that CLA as a whole oxidized rapidly and more than 80% was degraded within 110 h in air at 50 degrees C. Four c,c-CLA isomers were most unstable followed by four c,t-CLA isomers. In contrast, four t,t-CLA isomers were relatively stable under the same experimental conditions. Both the oxygen consumption and the GLC analysis revealed that 200 ppm jasmine green tea catechins (GTCs) exhibited protection to CLA and were even stronger than 200 ppm butylated hydroxytoluene (BHT) when added to either CLA or canola oil containing 10% CLA. The present study emphasized that oxidative unstability of CLA should not be overlooked although CLA has many biological effects.
Antioxidants↗
Induction of apoptosis and inhibition of NF-kappaB activation in human prostate cancer cells by the cis-9, trans-11 but not the trans-10, cis-12 isomer of conjugated linoleic acid.
BACKGROUND: Conjugated linoleic acids (CLAs) have anti-tumorigenic properties in animal models and anti-proliferative effects on cancer cells in vitro. Previous studies have shown that the NF-kappaB pathway is involved regulating anti-apoptotic gene expression. The present study investigated the effects of CLAs (cis-9, trans-11, and trans-10, cis-12 isomers and a 50:50 mixture) on apoptosis and NF-kappaB activation in LNCaP cells. METHODS: Apoptosis was assessed by annexin V staining using flow cytometry. TNF-alpha-induced NF-kappaB activity was determined by gel shift and reporter gene assays in addition to monitoring IkappaBalpha phosphorylation. RESULTS: Only the CLA cis-9, trans-11 isomer significantly increased TNF-alpha-induced apoptosis (by 59%), which correlated with a reduction in NF-kappaB transcriptional activity (by 35%, P < 0.05), NF-kappaB binding activity (by 15%, P < 0.05), and phosphorylation of IkappaBalpha (by 36%, P < 0.01). CONCLUSIONS: Our results may offer a mechanistic explanation for the reported inhibition of prostate tumor growth by CLAs in animal models of disease.
Annexin A5↗
Arachidonic acid does not share the antihypertensive properties of linoleic acid and fish oil omega-3 fatty acids in a model of angiotensin II-induced hypertension in the rat.
Linoleic acid and fish oil omega-3 fatty acids, but not arachidonic acid, exerted antihypertensive effects in a model of angiotensin II-induced hypertension in rats. Indomethacin did not influence the systolic arterial pressure of arachidonic acid-treated hypertensive rats whereas compound L-641,953, a prostaglandin H2/thromboxane A2 receptor antagonist, caused a notable but statistically nonsignificant decrease in blood pressure in these animals. Although these results do not exclude entirely the possibility that the lack of antihypertensive effect of arachidonic acid may be due, in part, to the concomitant formation of vasoconstrictor prostanoids, they do not support it. These observations, as well as those of a previous study, indicate that linoleic acid and fish oil omega-3 fatty acids exert antihypertensive effects of their own, independently of the prostanoid system, and that these properties are not shared by arachidonic acid.
6-Ketoprostaglandin F1 alpha↗
Inhibition of angiogenesis by the cancer chemopreventive agent conjugated linoleic acid.
Dietary conjugated linoleic acid (CLA) has been shown previously to inhibit rat mammary carcinogenesis. In addition to direct effects on mammary epithelial cells,including decreased proliferation and induction of apoptosis, CLA may exert its effects indirectly by inhibiting the differentiation of mammary stromal cells to an endothelial cell type. Specifically, CLA was found to decrease the ability of mammary stromal cells to form complex anastomosing microcapillary networks in vitro on Engelbreth-Holm-Swarm-derived reconstituted basement membrane. This suggested that CLA might inhibit angiogenesis in vivo. To test this possibility, CD2/F(1) mice were placed on synthetic diets containing 0, 1, or 2% CLA for 6 weeks, before angiogenic challenge by s.c. injection with an angiogenic gel substrate (Matrigel pellet assay). After 7 days, the pellets from animals fed the control diet were infiltrated by abundant branching networks of blood vessels with patent lumen-containing RBCs. In contrast, pellets from the CLA-fed animals contained fewer infiltrating cells, which formed limited branching cellular networks, the majority of which had collapsed lumen and no RBCs. Both levels of dietary CLA showed similar effects, with the number of RBC-containing vessels per 20x field decreased to a third of that seen in control. Dietary CLA decreased serum levels of vascular endothelial growth factor (VEGF) and whole mammary gland levels of VEGF and its receptor Flk-1. Both cis-9, trans-11 and trans-10, cis-12 CLA isomers were effective in inhibiting angiogenesis in vitro in a dose-dependent fashion. The ability of CLA to inhibit angiogenesis may contribute to its efficacy as a chemopreventive agent.
Angiogenesis Inhibitors↗