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PubMed2004

Conjugated linoleic acid blocks estrogen signaling in human breast cancer cells.

Conjugated linoleic acid (CLA), a mixture of positional and geometric isomers of linoleic acid found in dairy products and meat from ruminants, has been widely shown to possess anticarcinogenic activity against breast cancer both in vitro and in animal models. However, little information is available concerning the mechanisms of the antitumor effects of these compounds. In this study, we investigated whether CLA has direct antiestrogenic activity in estrogen receptor positive (ER+) breast cancer cells. Treatment of the ER+ cell line, MCF-7, with 5 purified CLA isomers as well as "mixed" CLA showed a dose-dependent growth inhibition with the 9cis,11cis and 9cis,11trans being the most and least potent isomers, respectively. In assessing effects on a number of variables that play obligatory roles in the estrogen signaling pathway, we determined that CLA treatment downregulated ERalpha expression at both mRNA and protein levels and decreased binding activity of nuclear protein to a canonical estrogen response element (ERE(v)). Using a reporter gene construct (ERE(v)-tk-Luc) that was transiently transfected into MCF-7 cells, we also demonstrated inhibition of promoter activity by CLA that was directly mediated by blockage of activity through the ERE. The results indicated that the order of potency of the CLA isomers for inhibiting activation of ERE(v) was similar to that demonstrated for their antiproliferative activity on MCF-7 cells. Taken together, these findings demonstrate that CLA compounds possess potent antiestrogenic properties that may at least partly account for their antitumor activity on breast cancer cells.

Actins↗
PubMed2002

Effect of dose of calcium salts of conjugated linoleic acid (CLA) on percentage and fatty acid content of milk fat in midlactation holstein cows.

Increasing conjugated linoleic acid (CLA) content of milk fat from lactating dairy cattle has become a research interest due to the possible health benefits afforded humans consuming CLA. Dietary supplementation of CLA to lactating dairy cows is one potential method by which CLA content of milk and dairy products may be enhanced. Feeding CLA in calcium salt form could potentially deliver CLA to the lower digestive tract through prevention of biohydrogenation by rumen microbes. Milk fat depression (MFD) occurs when cows receive CLA-60, a commercially available CLA source containing numerous CLA isomers, abomasally. Our objectives were to determine the quantity of CLA as calcium salts required to elicit maximal MFD and to evaluate the effects of CLA supplementation on fatty acid composition of milk fat. Five Holstein cows at approximately 93 DIM were utilized in a 5 x 5 balanced Latin square crossover design. Periods were 14-d in length with a 5-d treatment phase and 9-d rest phase. Treatments were 5-d supplementation of 0, 12.5, 25, 50, and 100 g of CLA-60 in calcium salt form. Milk samples were collected on d 5 of CLA supplementation and analyzed for composition and fatty acid profile. Regression analysis of milk fat data suggested that MFD was not maximized over the dose levels investigated, despite delivery of 34.5 g of trans-10, cis-12 CLA in the 100-g dose of CLA. Supplementation with 50 and 100 g of CLA per day resulted in a reduction of milk fat percent of 29 and 34%, respectively. Trend analysis indicated a linear decrease in the milk fat content of caprylic, capric, and lauric acids as the dose of CLA increased. Milk fat content of cis-9, trans-11, and trans-10, cis-12 CLA increased at an increasing rate as dose increased.

Animals↗
PubMed2002

Linoleic acid supplementation of Barth syndrome fibroblasts restores cardiolipin levels: implications for treatment.

The object of this study was to investigate whether the levels of cardiolipin in cultured skin fibroblasts of patients with Barth syndrome (BTHS) can be restored by addition of linoleic acid to growth media. To this end, fibroblasts from controls and BTHS patients were grown in the presence or absence of linoleic acid. High-performance liquid chromatography-electrospray ionization tandem mass spectrometry was used for quantitative and compositional analysis of cardiolipin. Incubation of cells from both BTHS and controls with different concentrations of linoleic acid led to a dose- and time-dependent increase of cardiolipin levels. The increased levels of cardiolipin in fibroblasts of BTHS patients after treatment with linoleic acid indicate that an increased amount of linoleic acid in the diet might be beneficial to BTHS patients.

Adolescent↗
PubMed1994

Linoleic acid and protein thiol changes suggestive of oxidative damage in the plasma of patients with adult respiratory distress syndrome.

Patients with the acute lung injury syndrome ARDS are under oxidative stress from the disease and from treatment with high inspired oxygen concentrations. Oxidative stress can lead to molecular damage by a variety of reactive oxygen intermediates generated in the lung. In the present study we sequentially monitor changes in plasma total lipid linoleic acid fatty acid levels, using GC-MS, and express these as a function of changes in plasma protein thiol values. In nine out of eleven ARDS patients there was a relationship between loss of protein thiols and loss of total lipid linoleic acid. In three patients changes in protein thiols preceded changes in total lipid linoleic acid by several days. Parallel decreases in plasma total lipid fatty acid esters of linoleic acid and protein thiols are suggestive of oxidative stress leading to molecular damage.

Blood Proteins↗
PubMed1999

Conjugated linoleic acid inhibits proliferation but stimulates lipid filling of murine 3T3-L1 preadipocytes.

This study documented the effects of conjugated linoleic acid (CLA) on the proliferation and differentiation of 3T3-L1 preadipocytes. During proliferation, preadipocytes were cultured in Dulbecco's modified Eagle's medium (DMEM), 100 g/L fetal bovine serum (FBS), 0. 584 g/L L-glutamine and 0 (control), 0.5, 1.0, 5.0 or 10.0 mg/L CLA. Proliferation of 3T3-L1 preadipocytes was measured directly by cell counting and indirectly by radiolabeled thymidine incorporation into DNA at 96 h postinoculation. Conjugated linoleic acid was not cytotoxic during proliferation or differentiation. The 0.5, 1.0, 5.0 or 10.0 mg/L CLA treatments inhibited proliferation by 8, 12, 31 and 36%, respectively (all P < 0.05). Treatment with 10 mg/L CLA or 10 mg/L linoleic acid (cis-9,12) reduced the incorporation of 3H-thymidine into DNA by 56 and 35%, respectively, suggesting that some portion of the effect of CLA on preadipocyte proliferation was nonspecific. After the initiation of differentiation, preadipocytes were cultured in DMEM, 100 g/L FBS, 0.584 g/L L-glutamine, 1.7 micromol/L insulin and 0 (control), 0.5, 1.0, 5.0 or 10.0 mg/L CLA. Radiolabeled glucose incorporation into cellular lipids was increased from 7.4 to 11.1, 11.1, 17.4 and 22.5 nmol/(h.10(6 )cells) (all P < 0.05) by 0.5, 1.0, 5.0 and 10.0 mg/L CLA, respectively. A media concentration of 10 mg/L CLA increased total cellular CLA (from 0 to 0.16 +/- 0.01 micromol/10(6 )cells), palmitic acid (from 0.47 to 1.10 +/- 0.03 micromol/10(6 )cells) and palmitoleic acid (from 0.24 to 0.81 +/- 0.03 micromol/10(6 )cells) (means +/- pooled SEM; all P < 0.05). Conjugated linoleic acid had no effect on arachidonic acid content, but decreased its proportion (g arachidonic acid/100 g total fatty acids) by >50% (P < 0.05). These data indicate that CLA inhibited proliferation and promoted de novo lipogenesis and lipid filling in 3T3-L1 preadipocytes, suggesting that CLA may reduce overall fat accumulation in growing animals by inhibiting stromal vascular preadipocyte hyperplasia.

3T3 Cells↗
PubMed1978

The role of holotrichs in the metabolism of dietary linoleic acid in the rumen.

The uptake and metabolism of linoleic acid by rumen holotrichs (mainly Isotricha prostoma and I. intestinalis) has been examined in in vitro infusion experiments. Maximum absorption and metabolism of [1-14C]linoleate by 2 . 10(6) Isotricha suspended in 100 ml buffer was obtained using an infusion rate of 1.6 mg linoleate/h. After 90 min, 84% of the added substrate was recovered within the cells, mainly as free fatty acid or phospholipid. There was a rapid incorporation of radioactivity into phospholipid, mainly phosphatidylcholine, at the commencement of linoleate infusion but no further incorporation after about 40 min. The presence of bacteria during incubations, in approximately the same Isotricha/bacteria ratio as found in the rumen, reduced the uptake of linoleate and the accumulation of free fatty acid by holotrichs but the incorporation into phospholipid remained similar to that obtained in the absence of bacteria. Very little biohydrogenation of linoleic acid occurred in incubations with holotrichs alone. Bacterial suspensions converted linoleic acid to mainly trans monoene and a small amount of stearic acid, but in incubations containing both bacteria and holotrichs, both stearic acid and trans monoene were major products. Using the latter mixed culture, about 20% of the added [1-14C]linoleic acid was present in holotrich phospholipid of which 62% remained as octadecadienoic acid. The Isotricha population was 3 . 10(3)--2 . 10(4)/ml rumen fluid and it contributed about 23% of the linoleic acid in the rumen of a cow on a hay diet.

Animals↗
PubMed2002

Inhibition of carcinogenesis by conjugated linoleic acid: potential mechanisms of action.

Conjugated linoleic acid (CLA) is composed of positional and stereoisomers of octadecadienoate (18:2); it is found in foods derived from ruminants (beef and lamb as well as dairy products from these sources). When a mixture of isomers is fed to experimental animals, chemically induced tumorigenesis of mammary, skin and colon is reduced. Importantly, many isomers of CLA are readily metabolized to desaturated/elongated products as well as beta-oxidized products, suggesting that these metabolites may be important anticancer compounds. Mechanisms of inhibition of carcinogenesis may include reduction of cell proliferation, alterations in the components of the cell cycle and induction of apoptosis. In addition, CLA modulates markers of immunity and eicosanoid formation in numerous species as well as lipid metabolism and gene expression. It is likely that CLA exerts inhibitory properties in carcinogenesis via one or more of these pathways with some tissue specificity. This review will explore recent advances in putative mechanisms of reduction of carcinogenesis by CLA.

Animals↗
PubMed1996

A novel approach to study linoleic acid autoxidation: importance of simultaneous detection of the substrate and its derivative oxidation products.

In this paper we have proposed a novel approach for studying the reaction of lipid oxidation by using the simplest chemical system available. Neat linoleic acid was incubated for 24 hours at 37 degrees C in the air. The course of lipid oxidation was followed by measuring simultaneously by HPLC with a diode array detector 1) linoleic acid decrease, 2) the products formed by radical attack, namely four hydroperoxy-octadeca-dienoic acid (HPODE) isomers, two c,t (c,t) and two trans,trans (t,t). 3) the byproducts formed by HPODE degradations, the four oxo-octadeca-dienoic acid (oxo-ODE) isomers. In HPODEs the presence of conjugated diene chromophore was confirmed by second derivative spectrophotometry. c,t HPODEs were also identified for their positional isomerism, while for t,t molecules the lack of suitable reference compound makes unfeasible the identification of their positional isomerism. As in the case of the latter two c,t and two t,t oxo-ODE isomers were characterized. This simple system appears to be useful for studying the activity exherted by lipophilic molecules that, like alpha-tocopherol, may act as antioxidants and/or as hydrogen atom donating molecules. The presence of alpha-tocopherol in different concentration for 24 hours in the reaction environment, shifts the reaction of linoleic acid autoxidation towards different byproduct formations. From the results obtained it is evident that alpha-tocopherol acts as hydrogen atom donor at all concentration tested, shifting the reaction toward a prevalent formation of c,t isomer of both HPODEs and oxo-ODEs. At concentration lower than 40 nmoles, when the ratio between alpha-tocopherol and linoleic acid was 1:100, the reaction of autoxidation is strongly inhibited, while at higher concentration alpha-tocopherol acted as a prooxidant. In these experimental conditions, alpha-tocopherylquinone was spectrophotometrically identified as the predominant oxidation product of alpha-tocopherol.

Chromatography, High Pressure Liquid↗
PubMed1980

Haemoprotein- and transition metal ion-catalysed oxidation of linoleic acid. Selectivity of the position of oxygenation.

Oxidation of linoleic acid in aqueous buffers favoured the formation of the 13 positional isomers of hydroperoxylinoleic acid. The reaction which was catalysed by haemoproteins and Fe(II) and Cu(II) ions showed positional selectivity that was similar to lipoxygenase-catalysed reactions but yielded equal proportions of both enantiomers of the hydroperoxides. There was little selectivity when methyl linoleate was used as the substrate or when linoleic acid was oxidised in organic solvents. The results indicated that positional selectivity was, at least in part, due to the conformation of the fatty acid molecule in aqueous media. Implication of the selectivity in a non-enzymic reaction is discussed especially in relation to its effect on the determination of lipoxygenase specificities.

Buffers↗
PubMed1998

Analysis of cytochrome P450 metabolites of arachidonic and linoleic acids by liquid chromatography-mass spectrometry with ion trap MS.

We have used reversed phase-high performance liquid chromatography-mass spectrometry (RP-HPLC-MS) with an ion trap mass spectrometer to study the metabolism of arachidonic and linoleic acids by human recombinant cytochrome P450 (CYP) enzymes. We first recorded the MS2 spectra of the carboxylate anions of epoxides, diols, omega-side chain, and bisallylic hydroxy fatty acids of arachidonic, octadeuterated arachidonic, and linoleic acids. The metabolites formed by CYP2C9 and CYP2C19 were then studied. CYP2C9 converted arachidonic and linoleic acids to epoxides/diols and monohydroxy fatty acids. Some hydroxyeicosatetraenoic acids (HETEs) were studied in detail to investigate the oxygenation mechanism. Incubation of CYP2C9 under oxygen-18 gas showed that all HETEs had incorporated oxygen-18 to the same degree. Chiral HPLC showed that CYP2C9 formed 15R-HETE (72% of the R enantiomer), 13S-HETE (90%), and 11R-HETE (57%). RP-HPLC-MS analysis revealed that CYP2C19 oxygenated arachidonic acid to 19-HETE, 14,15-epoxyeicosatrienoic acid (EET), and 8,9-EET as main metabolites. The method was sufficiently sensitive to identify arachidonic acid metabolites formed by some other isozymes. RP-HPLC-MS with MS2 seems to be useful for rapid identification of fatty acid metabolites in complex mixtures formed by cytochrome P450.

Arachidonic Acids↗
PubMed2003

Effects of conjugated linoleic acid on body fat accumulation and serum lipids in hamsters fed an atherogenic diet.

Conjugated linoleic acid (CLA) refers to a mixture of naturally occurring positional and geometric isomers of linoleic acid that exist in dairy products and meat. The aim of the present work was to study the effects of c-9,t-11 and t-10,c-12 CLA isomers on body fat accumulation and serum lipids in hamsters fed an atherogenic diet. Hamsters were divided in four groups: one group was fed a chow diet (control) and the other three groups were given semi-purified atherogenic diets with 0.5% linoleic acid (LA), c-9,t-11 or t-10,c-12 CLA. Body weight and food intake were measured daily. After 6 weeks, adipose tissues from different anatomical locations and liver were dissected and weighed. Serum glucose, total cholesterol, HDL-c, LDL-c and triacylglycerol levels, as well as total and free cholesterol, triacylglycerol and phospholipid content in liver were determined by enzymatic methods. No differences in either energy intake or final body weight were found. The addition of t-10,c-12 CLA reduced fat accumulation and led to lower serum cholesterol, as compared with LA group. Nevertheless the level remained higher than in the control animals. The reduction in serum cholesterol was limited to LDL-c. This isomer also reduced triacylglycerol content in liver but did not modify serum triacylglycerol level. In summary, the present study demonstrates that t-10,c-12 CLA is the biologically active agent when anti-obesity and hypocholesterolaemic properties of CLA are considered. In contrast, the isomer c-9,t-11 has no effect on lipid metabolism in hamsters.

Adipose Tissue↗
PubMed1996

Dietary protein modifies oxidized cholesterol-induced alterations of linoleic acid and cholesterol metabolism in rats.

Effects of dietary protein on oxidized cholesterol-induced alterations in linoleic acid and cholesterol metabolism were studied in 4-wk-old male Sprague-Dawley rats, using casein and soybean protein as dietary protein sources. The rats were fed one of the two proteins in cholesterol-free, 0.3% cholesterol or 0.3% oxidized cholesterol mixture diets using a pair-feeding protocol for 3 wk. In the soybean protein-fed group, rats fed oxidized cholesterol did not have lower activity of liver microsomal delta6 desaturase, the rate-limiting enzyme in the metabolism of linoleic acid to arachidonic acid, compared with rats fed cholesterol-free diet, whereas in the casein-fed group the desaturase activity was significantly greater in rats fed oxidized cholesterol than in those fed cholesterol-free diet. This was in contrast to a significant reduction in liver microsomal delta6 desaturase activity by cholesterol, irrespective of protein source. In general, these changes were reflected in the desaturation indices of liver phospholipids. Furthermore, soybean protein significantly increased the fecal excretion of neutral and acidic steroids and tended to reduce (P = 0.082) the accumulation of oxidized cholesterols in the liver. Thus, soybean protein partly modified some of the undesirable effects of oxidized cholesterol through its hypocholesterolemic effect and possibly through the modulation of hepatic delta6 desaturase activity.

Animals↗
PubMed2004

Effect of linoleic acid on proliferation and gene expression in the breast cancer cell line T47D.

Human and animal studies have linked n-6 polyunsaturated fatty acids with mammary carcinogenesis. We investigated the cellular and molecular effects of linoleic acid on the human breast cancer cell line T47D. Linoleic acid had a stimulatory effect on the growth of T47D cells, associated with an increase in the proportion of cells in the S phase of the cell cycle. Microarray, functional group and quantitative PCR analyses indicate that linoleic acid may affect T47D cell growth by modulation of the estrogen receptor (ERalpha), the G13alpha G protein, and p38 MAP kinase gene expression as well genes involved in RNA transcription and cell cycle regulation.

Cell Division↗
PubMed2002

Dietary trans-10,cis-12 conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse.

Conjugated linoleic acids (CLA) are a class of positional, geometric, conjugated dienoic isomers of linoleic acid (LA). Dietary CLA supplementation results in a dramatic decrease in body fat mass in mice, but also causes considerable liver steatosis. However, little is known of the molecular mechanisms leading to hepatomegaly. Although c9,t11- and t10,c12-CLA isomers are found in similar proportions in commercial preparations, the respective roles of these two molecules in liver enlargement has not been studied. We show here that mice fed a diet enriched in t10,c12-CLA (0.4% w/w) for 4 weeks developed lipoatrophy, hyperinsulinemia, and fatty liver, whereas diets enriched in c9,t11-CLA and LA had no significant effect. In the liver, dietary t10,c12-CLA triggered the ectopic production of peroxisome proliferator-activated receptor gamma (PPARgamma), adipocyte lipid-binding protein and fatty acid transporter mRNAs and induced expression of the sterol responsive element-binding protein-1a and fatty acid synthase genes. In vitro transactivation assays demonstrated that t10,c12- and c9,t11-CLA were equally efficient at activating PPARalpha, beta/delta, and gamma and inhibiting liver-X-receptor. Thus, the specific effect of t10,c12-CLA is unlikely to result from direct interaction with these nuclear receptors. Instead, t10,c12-CLA-induced hyperinsulinemia may trigger liver steatosis, by inducing both fatty acid uptake and lipogenesis.

Adipose Tissue↗
PubMed2004

Jejunal administration of linoleic acid increases activity of neurons in the paraventricular nucleus of the hypothalamus.

The present experiment examined whether neurons located in the paraventricular nucleus of the hypothalamus (PVN) respond to intestinal infusions of long-chain fatty acids. Single-unit recordings were made of neurons located in and adjacent to the PVN during jejunal administration of linoleic acid. Jejunal administration of linoleic acid increased single-unit activity of neurons located in the PVN but did not affect activity of neurons located in adjacent tissue outside the PVN. The largest increases in neuronal activity were observed in the anterior PVN (0.9-1.3 mm posterior to bregma) compared with the posterior PVN (1.8-2.1 mm posterior to bregma). Jejunal administration of saline failed to affect activity of neurons located either inside or outside the PVN. When the same neurons were subsequently tested for their response to intravenous administration of 2 microg/kg of CCK-8, excitatory responses were more frequently observed than inhibitory responses, but both types of responses were observed regardless of whether neurons were located inside or outside the PVN. In addition, there was no strong correlation between the magnitude of the neuronal response evoked by jejunal administration of linoleic acid compared with intravenous CCK-8. These data suggest that neurons located in the anterior PVN may play a role in the mediation of suppression of food intake produced by intestinal administration of lipids.

Animals↗
PubMed2006

Intestinal bifidobacteria that produce trans-9, trans-11 conjugated linoleic acid: a fatty acid with antiproliferative activity against human colon SW480 and HT-29 cancer cells.

Bifidobacterium breve species of human intestinal origin have the ability to synthesize cis-9, trans-11 (c9, t11) conjugated linoleic acid (CLA) from free linoleic acid. In this study, the ability of Bifidobacterium species to isomerize C(18) polyunsaturated fatty acids was investigated, and the antiproliferative activities of the two main microbially produced CLA isomers were assessed. Linoleic acid was converted principally to c9, t11 CLA and lesser amounts of t9, t11 CLA, whereas c9, t11 CLA was converted mainly to t9, t11 CLA. Likewise, t10, c12 CLA was converted principally to t9, t11 CLA, which was incorporated into the bacterial cell membranes. To examine the antiproliferative effect of the two main CLA isomers formed, SW480 and HT-29 human colon cancer cells were cultured in the presence of c9, t11 CLA and t9, t11 CLA. The t9, t11 CLA had a more potent antiproliferative effect than c9, t11 CLA. It is tempting to suggest that the ability of Bifidobacterium to produce such bioactive metabolites may be associated with the beneficial effects of bifidobacteria present in the human gastrointestinal tract.

Antineoplastic Agents↗
PubMedDate not supplied

[The effect of a diet with different contents of linoleic acid on the development of alcoholic liver diseases].

White rats received rations with varying content of linoleic acid (3.17 and 90 g/kg of food) during 30 days. The control rats that received food with low content of linoleic acid showed a higher content of triglycerides in the liver. Elevation of linoleic acid level in the ration of animals with chronic alcoholic intoxication diminishes the symptoms of alcoholic hepatosis: hepatocyte vacuolization and the content of neutral lipids in them are lowered, serum enzyme (alanine-aminotransferase, gamma-glutamyltransferase) activity decreases as well as the signs of essential fatty acid deficiency disappear.

Animals↗
PubMed2003

Fatty acid composition and productive traits of broiler fed diets containing conjugated linoleic acid.

An experiment was carried out to evaluate the transfer of dietary CLA to broiler chicken tissues (breast, drumstick meat, skin, and abdominal fat) and its effect on productive traits and on carcass yields of birds. Cobb 500 females (n=360), divided into three groups, received from 22 d to slaughtering age (47 d) a grower diet supplemented with 2% conjugated linoleic acid (CLA) source containing 60% CLA methyl esters (CLA2) or 4% CLA source (CLA4). The control group had no supplementation. The addition of CLA source to chicken diet decreased the content of monounsaturated fatty acid (MUFA) (oleic and palmitoleic acids) in breast and drumstick meat. The deposition of CLA in muscles significantly increased as the dietary CLA increased, whereas only little amounts of CLA were detected in the control group. Arachidonic acid (ARA) content was significantly depressed and linearly related to the addition of CLA to the chicken diet. Other non-CLA polyunsaturated fatty acids (PUFA) were little affected by the dietary CLA supplementation. Saturated fatty acids (myristic and stearic acids) significantly increased about 30% in abdominal fat pad of both treated groups enhancing the firmness of abdominal fat. Productive performances--as well as carcass yields--were similar across dietary treatment of birds.

Animals↗