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PubMed2005

Role of the conjugated linoleic acid in the prevention of cancer.

There are multiple lines of evidence that a variety of natural fatty acids are effective in health promotion. Among these fatty acids, conjugated linoleic acid (CLA)--a collective term referring to a mixture of positional and geometric isomers of linoleic acid (LA, cis-9, cis-12-octadecadienoic acid)--is currently under intensive investigation due to its health-promotion potential. The antitumor activity of CLA is of special interest, since it shows inhibitory effects against multistage carcinogenesis at relatively low dietary levels. Many studies using in vivo and in vitro models have shown that CLA suppresses the development of multistage carcinogenesis at different sites. The research to date on CLA has provided a vast amount of information about the mechanism on how CLA functions in the prevention of cancer. This article discusses characteristics of CLA in the prevention of cancer in both in vivo and in vitro studies and the possible underlying chemoprevention mechanisms.

Animals↗
PubMed1997

Conjugated linoleic acid modulation of phorbol ester-induced events in murine keratinocytes.

Recent work in our lab has shown that the chemoprotective fatty acid, conjugated linoleic acid (CLA), inhibits phorbol ester skin tumor promotion in mice. Because little is known about the deposition of CLA into tissues as well as its biological activity, this study compared the incorporation and biological activity of CLA to linoleic acid (LA; 18:2, c9,c12) and arachidonic acid (AA; 20:4 c5,c8,c11,c14) in cultured keratinocytes. When keratinocytes (HEL-30) were grown in media containing 14C-CLA for various periods, more than 50% of the 14C-CLA was incorporated into cellular lipids by 9 h. The distribution of CLA in phospholipid classes was similar to LA, Approximately 50% of 14C-LA and 14C-CLA were incorporated into phosphatidylcholine (PC), while the remainder was taken up by phosphatidylethanolamine (PE) and phosphatidylserine/phosphatidylinositol (PS/PI). In contrast, 14C-AA was more equitably distributed into PC, PE, or PS/PI (27, 30, or 38%, respectively). When keratinocytes were prelabeled with radiolabeled fatty acids, phorbol ester-induced release of 14C-CLA was 1.5 times higher than 14C-LA and 14C-AA. However, 14C-prostaglandin E (PGE) release in 14C-CLA prelabeled cultures was 6 and 13 times lower than cultures treated with 14C-LA and 14C-AA, respectively. Moreover, the ability of non-radiolabeled CLA to support ornithine decarboxylase activity, a hallmark event of tumor promotion, was significantly lower than in LA- and AA-treated cultures. These studies suggest that CLA inhibits skin tumor promotion, in part, through a PGE-dependent mechanism.

Animals↗
PubMed1980

The permeability barrier in essential fatty acid deficiency: evidence for a direct role for linoleic acid in barrier function.

Essential fatty acid (EFA) deficient rodents demonstrate abnormal epidermal permeability barrier function and differentiation, defects which can be corrected by either topical or systemic administration of linoleic acid. Since linoleic acid is a precursor of prostaglandins, correction of the defect in barrier function may either reflect a prostaglandin-mediated return toward normal epidermal differentiation, or, instead, a direct effect of linoleic acid. To test these possibilities severely EFA-deficient mice were pretreated daily with indomethacin and/or 5,8,11,14-eicosatetrayeonic acid, and then placed on normal (lineolic acid-supplemented) diets. Endogenous formation of prostaglandin E2 was determined by thin-layer chromatography after transformation into prostaglandin B2 with ethanolic-hydrochloric acid. Animals treated with both indomethacin and TYA DEMONSTRATED SUBSTANTIAL REDUCTIONS IN PROSTAGLANDIN E2 levels in liver and skin. Animals replenished with linoleic acid invariably demonstrated a rapid return of barrier function toward normal whether or not they were blockaded, while nonreplenished animals, with or without inhibition of prostaglandin biosynthesis, demonstrated continued deterioration in barrier function. In other experiments, topically applied linoleic acid rapidly reversed the defect in barrier function at the sites of application prior to systemic correction of the EFA deficient state. These results suggest that: (1) defective cutaneous barrier function in EFA deficiency can be corrected locally without prior systemic reversal of the deficiency state; and (2) that linoleic acid may play a direct role in the epidermal permeability barrier independent of its role in prostaglandin metabolism.

Animals↗
PubMed1998

Exogenous conjugated linoleic acid isomers reduce bovine milk fat concentration and yield by inhibiting de novo fatty acid synthesis.

Conjugated linoleic acid (CLA) is a potent anticarcinogen secreted in milk of ruminants, but it inhibits de novo fatty acid synthesis and desaturation in mammary cell cultures. The potential for increasing CLA content of milk fat and the effects of elevated CLA availability on milk fat secretion were investigated. Four Holstein cows were used in a single crossover design with repeated measures to determine milk fatty acid concentration in response to a 24-h infusion of 200 g linoleic acid (LA) or a mixture of 100 g LA plus 100 g CLA (LCLA). Milk and blood samples were obtained 12 h before infusion and at 12-h intervals from 0 to 72 h. Compared with LA infusion, total CLA concentration in blood plasma at 24 h in response to LCLA was elevated fivefold, whereas CLA content of plasma triglycerides was increased 10-fold. Milk fat yield from 24 to 72 h was approximately 34% lower in response to LCLA compared with LA, due primarily to reduced yield of fatty acids with six to 16 carbons. Amount of CLA in milk increased from 0.5 g/100 g total fatty acids at 0 h to 3.3 g/100 g at 36 h in response to LCLA. Concentration of stearic acid in milk fat at 36 h in response to LCLA was nearly double the stearic acid concentration in response to LA. Oleic and arachidonic acid concentrations in milk declined as stearic acid increased in response to LCLA. Results indicated CLA content of milk fat reflects the amount available for absorption from the small intestine, and CLA appeared to be a potent inhibitor of de novo fatty acid synthesis and desaturation in the mammary gland.

Abomasum↗
PubMed2003

Involvement of CYP 2C9 in mediating the proinflammatory effects of linoleic acid in vascular endothelial cells.

OBJECTIVE: Polyunsaturated fatty acids such as linoleic acid are well known dietary lipids that may be atherogenic by activating vascular endothelial cells. In the liver, fatty acids can be metabolized by cytochrome P450 (CYP) enzymes, but little is known about the role of these enzymes in the vascular endothelium. CYP 2C9 is involved in linoleic acid epoxygenation, and the major product of this reaction is leukotoxin (LTX). We investigated the role of CYP-mediated mechanisms of linoleic acid metabolism in endothelial cell activation by examining the effects of linoleic acid or its oxidized metabolites such as LTX and leukotoxin diol (LTD). METHODS: The effect of linoleic acid on CYP 2C9 gene expression was studied by RT-PCR. Oxidative stress was monitored by measuring DCF fluorescence and intracellular glutathione levels, and electrophoretic mobility shift assay was carried out to study the activation of oxidative stress sensitive transcription factors. Analysis of oxidized lipids was carried out by liquid chromatography/mass spectrometry. RESULTS: Linoleic acid treatment for six hours increased the expression of CYP 2C9 in endothelial cells. Linoleic acid-mediated increase in oxidative stress and activation of AP-1 were blocked by sulfaphenazole, a specific inhibitor of CYP 2C9. The linoleic acid metabolites LTX and LTD increased oxidative stress and activation of transcription factors only at high concentrations. CONCLUSION: Our data show that CYP 2C9 plays a key role in linoleic acid-induced oxidative stress and subsequent proinflammatory events in vascular endothelial cells by possibly causing superoxide generation through uncoupling processes.

Animals↗
PubMed1976

Comparative effect of glucagon, dibutyryl cyclic AMP, and epinephrine on the desaturation and elongation of linoleic acid by rat liver microsomes.

The effect of glucagon, dibutyryl cyclic adenosine 3',5'-monophosphate, and epinephrine on the biosynthesis of polyunsaturated fatty acids of the linoleic acid family was studied. The incubations were performed with rat liver microsomes and labeled linoleic acid under desaturating and elongating conditions. Under desaturating conditions linoleic acid was converted to gamma-linolenic acid, whereas under elongating conditions it was converted to 20:2omega6. Glucagon, dibutyryl cyclic AMP, and epinephrine decreased the oxidative desaturation of linoleic acid to gamma-linolenic acid while the elongating reaction was not modified in the experimental conditions tested. Consequently, the results support the hypothesis that the oxidative desaturation of linoleic acid to gamma-linolenic acid is the main controllable step in the biosynthesis of polyunsaturated fatty acids of the linoleic acid family in the microsomes.

Animals↗
PubMed1987

Protection of the gastric mucosa by linoleic acid--a nutrient essential fatty acid.

We studied whether linoleic acid, a precursor for arachidonic acid and prostaglandins, could protect the gastric mucosa against ethanol-induced injury. Fasted male rats received intragastric pretreatment with 1 ml of one of: a) solubilizer; b) solubilized linoleic acid (74 mg); or c) solubilized oleic acid (74 mg) (a nonessential fatty acid). One hour later, 2 ml 100% ethanol was given intragastrically. Three hours after ethanol administration, the gastric mucosa was assessed for gross necrosis and for histologic changes. Three hours after ethanol administration in solubilizer, pretreated-group gross mucosal necrosis involved 35 +/- 3% of total mucosal area, while deep histologic necrosis involved 52 +/- 4% of the mucosal strip length. Pretreatment with linoleic acid (but not oleic acid) significantly reduced gross histologic necrosis, to 2.3 +/- 0.5%, and deep histologic necrosis to 4 +/- 2% (both p less than 0.001 versus solubilizer group). The protective action of linoleic acid was significantly reduced (greater than 10-fold) by pretreatment with indomethacin (prostaglandins synthetase inhibitor), suggesting prostaglandins as mediators of protection. The present study showed that effective protection of the gastric mucosa against ethanol injury can be achieved by intragastric administration of linoleic acid, a dietary essential fatty acid.

Animals↗
PubMed1991

Effects of eicosapentaenoic acid and arachidonic acid on incorporation and metabolism of radioactive linoleic acid in cultured human fibroblasts.

Effects of exogenous eicosapentaenoic acid, arachidonic acid and oleic acid on incorporation and metabolism of [14C] linoleic acid were examined in cultured human fibroblasts obtained from three donors of different ages. Eicosapentaenoic acid treatment (40 microM) inhibited incorporation of radioactive linoleic acid and actively reduced radioactivity of desaturation-elongation metabolites in phospholipids, predominantly in the phosphatidylethanolamine fraction. In contrast, radioactivities of the metabolites in triacylglycerols were significantly increased with arachidonic acid treatment (40 microM): eicosapentaenoic acid had a smaller effect or none. Oleic acid had virtually no effect. These effects were consistent in the three cell lines, but responses to treatment with the acids differed considerably among individual cells. The pool of linoleic acid metabolites in triacylglycerols may not be negligible. The exogenous fatty acids may influence both the transfer of lipids between the major lipid pools as well as the activities of the desaturation-elongation system.

Arachidonic Acid↗
PubMed2002

Conjugated linoleic acid metabolism.

Conjugated linoleic acid (CLA) is a naturally occurring fatty acid that is produced by a bio-hydrogenation process in the rumen, and thus is present in dairy products and ruminant meat. In this case the predominant isomer formed is 9cis,11trans. However, CLA includes 28 positional and geometrical isomers, of which only 9cis,11trans and 10trans,12cis have thus far been proven to possess biological activities. Both of these CLA isomers have been shown to undergo elongation and desaturation processes similar to those that occur with linoleic acid, maintaining the conjugated diene structure. There are evidences supporting the hypothesis that CLA metabolism may interfere with eicosanoid formation. Other metabolites with 16 carbon atoms (conjugated 16:2 and 16:3, which are probably derived from peroxisomal beta-oxidation of CLA and its metabolites, respectively) have been detected. This suggests an efficient metabolism of CLA and its metabolites in peroxisomes, which might be linked to their capacity to activate peroxisome proliferator-activated receptors.

Animals↗
PubMed1986

Plasma fatty acid pattern including diene-conjugated linoleic acid in ethanol users and patients with ethanol-related liver disease.

The level of conjugated dienes (CD) in the serum, conjugated linoleic acid isomer in the phospholipid fraction [18:2(9, 11)], and the fatty acid profile in both the serum and in the separated lipid classes were analyzed in current and previous alcohol abusers and in patients with alcoholic liver disease. None of the subjects consumed alcohol for at least 2-3 days prior to blood collection for analysis of lipids. There was no significant difference in CD or in the absolute level of 18:2(9, 11) among the groups, whereas the 18:2(9, 11)/18:2(9, 12) molar ratio was significantly elevated in patients with liver disease. Fatty acid analysis of the whole plasma extract showed that the absolute level of arachidonic acid increased from 4.8 +/- 3.5 mg/dl (n = 9) in lifelong abstainers to 13.4 +/- 4.0 (n = 8) in current ethanol abusers, and its relative level (related to the total fatty acids) from 1.73 +/- 1.34 to 4.55 +/- 1.01 in the same groups. An increased proportion of linoleic acid in the triglyceride and phospholipid fractions from current abusers and patients with liver disease was also found; the percentage of 18:2 in phospholipids increased from 5.4 +/- 5.0 (n = 8) in lifelong abstainers to 14.3 +/- 3.9 (n = 8) in current abusers and 12.7 +/- 2.2 (n = 10) in patients with liver disease. The percentage of 16:0 was significantly lower in the phospholipids of current abusers as compared to lifelong abstainers.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

Stimulation of cell proliferation and inhibition of gap junctional intercellular communication by linoleic acid.

The effect of linoleic acid (LA) on gap-junction permeability, connexin 43 mRNA level, protein level, and phosphorylation, and the numbers of gap-junctional membrane plaques were studied in the rat liver epithelial cell line WB-F344 to determine whether changes in these parameters correlated with the enhanced cell growth and the inhibition of gap-junction function. When cultured in a medium with low serum (1%), these cells exhibited a slower growth rate than in the high serum medium (7%). Addition of linoleic acid (0.01-3 mg/ml) to the low serum medium increased the growth rate and inhibited gap junctional intercellular communication (GJIC) in a dose-dependent manner. In a comparison of short-term and long-term treatments with LA, GJIC in short-term treated (1 h) WB cells was inhibited at 3 mg/ml LA but readily recovered by washing and removing LA from cells, whereas GJIC in long-term treated (6 days) WB cells did not recover by washing and removing LA from WB cells. Western blot analysis of connexin 43 showed that a short-term incubation with linoleic acid increased the relative amount of unphosphorylated connexin 43 protein, but a long-term incubation with linoleic acid decreased the amount of unphosphorylated connexin 43 protein and increased the relative amount of hyperphosphorylated connexin 43 protein. Connexin 43 and p53 mRNA levels decreased in a time- and dose-dependent manner in linoleic acid-treated cells. These results suggest that growth stimulation and gap junctional intercellular communication inhibition of rat liver epithelial cells by linoleic acid may be mediated in part through modulation of p53 expression and function.

Animals↗
PubMed2001

Linoleic acid partially restores the triglyceride content of conjugated linoleic acid-treated cultures of 3T3-L1 preadipocytes.

We have previously demonstrated that a crude mixture of commercially available conjugated linoleic acid (CLA) isomers suppressed triglyceride (TG) content and induced apoptosis in post-confluent cultures of murine 3T3-L1 preadipocytes. Furthermore, we found that 100 &mgr;M of trans-10, cis-12 isomer of CLA had a greater TG-lowering and apoptotic effect than the crude mixture of CLA isomers. Therefore, the purpose of this study was to: 1) compare the potencies of the two main isomers found in the crude mixture of CLA isomers, e.g. cis-9, trans-11 (41%) and trans-10, cis-12 (44%); and 2) determine if the TG-reducing actions of CLA could be attenuated by the addition of increasing levels of linoleic acid to the cultures. Preadipocyte differentiation was assessed on day 7 of the differentiation protocol by measuring TG content (per 10(6) cells), cell size, and lipid staining. In experiment 1, post-confluent cultures of 3T3-L1 preadipocytes treated for the first 6 d of differentiation with 100 &mgr;M of a crude mixture of CLA isomers or 44 &mgr;M of trans-10, cis-12 CLA had less TG content than all other cultures. In contrast, cultures supplemented with 41 &mgr;M of the cis-9, trans-11 CLA isomer had the same amount of TG as the BSA controls. In experiment 2, post-confluent cultures of 3T3-L1 preadipocytes treated for the first 6 d of differentiation with 50 &mgr;M trans-10, cis-12 CLA had less TG content and a greater number of smaller cells (10-12.5 microns) compared to all other treatments. CLA-treated cultures supplemented with increasing levels of linoleic acid (50-200 &mgr;M) had greater TG contents and greater numbers of larger cells (15-20 microns) than cultures treated with 50 &mgr;M of the trans-10, cis-12 CLA isomer alone. These data demonstrate that: 1) the TG-lowering effects of the crude mixture of CLA isomers is due almost exclusively to the trans-10, cis-12 isomer; and 2) linoleic acid partially reverses CLA's attenuation of TG content, suggesting that these unsaturated fatty acids may compete for incorporation into TG or phospholipid-derived eicosanoids that regulate preadipocyte differentiation.

Journal Article↗
PubMed2006

Biological effects of conjugated linoleic acids in health and disease.

Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of octadecadienoic acid [linoleic acid (LA), 18:2n-6] commonly found in beef, lamb and dairy products. The most abundant isomer of CLA in nature is the cis-9, trans-11 (c9t11) isomer. Commercially available CLA is usually a 1:1 mixture of c9t11 and trans-10, cis-12 (t10c12) isomers with other isomers as minor components. Conjugated LA isomer mixture and c9t11 and t10c12 isomers alone have been attributed to provide several health benefits that are largely based on animal and in vitro studies. Conjugated LA has been attributed many beneficial effects in prevention of atherosclerosis, different types of cancer, hypertension and also known to improve immune function. More recent literature with availability of purified c9t11 and t10c12 isomers suggests that t10c12 is the sole isomer involved in antiadipogenic role of CLA. Other studies in animals and cell lines suggest that the two isomers may act similarly or antagonistically to alter cellular function and metabolism, and may also act through different signaling pathways. The effect of CLA and individual isomers shows considerable variation between different strains (BALB/C mice vs. C57BL/6 mice) and species (e.g., rats vs. mice). The dramatic effects seen in animal studies have not been reflected in some clinical studies. This review comprehensively discusses the recent studies on the effects of CLA and individual isomers on body composition, cardiovascular disease, bone health, insulin resistance, mediators of inflammatory response and different types of cancer, obtained from both in vitro and animal studies. This review also discusses the latest available information from clinical studies in these areas of research.

Animals↗
PubMed2002

Polyunsaturated fatty acid biosynthesis from [1-14C]20:3 n-6 acid in rat cultured Sertoli cells. Linoleic acid effect.

Primary culture is a suitable system to study lipid metabolism and polyunsaturated fatty acid biosynthesis. Sertoli cell-enriched preparations were used to determine the fatty acid composition after 5 and 7 days in culture (serum free) as well as the uptake and metabolism of [1-14C]eicosa-8,11,14-trienoic acid. The addition of unlabeled linoleic acid (0.2 and 2.0 microg/ml) was also evaluated. Fatty acid methyl esters derived from cellular lipids were analyzed by gas liquid chromatography and radiochromatography. After 5 days in culture, cells had significantly less 18:2, 20:4, 22:5 and 24:5 and more 18:3, 20:3, 22:4 and 24:4 n-6 fatty acids than non-cultured cells. On day 7, an additional increment in 22:4 n-6 and a decrease in linoleic, gamma-linoleic and 24:4 n-6 fatty acids were observed. The presence of linoleic acid (low dose) produced a significant decrease in saturated and monounsaturated acids and an increase in 18:2, 20:4 and 22:5 n-6 fatty acids. At a high concentration almost all fatty acids belonging to 18:2 n-6 increased significantly. The drop in 20:4 n-6/20:3 n-6 ratio was considered as an indirect evidence of a Delta 5 desaturase activity depression. This assumption was corroborated by studying the transformation of [1-14C]eicosa-8,11,14-trienoic acid into 20:4, 22:4, 22:5, 24:4 and 24:5 n-6 fatty acids. We conclude that Sertoli cells after 7 days in culture evidenced changes in the fatty acid profile similar to those described under fat deprivation. The addition of linoleic acid reverted this pattern and indicated that the Delta 5 desaturase activity is a limiting step in the polyunsaturated fatty acid biosynthesis.

8,11,14-Eicosatrienoic Acid↗
PubMed1985

Calcium-translocating and cardiotonic properties of oxidation products of linoleic acid.

Calcium-translocating activity of linoleic acid and its lipoxygenase (linoleate: oxygen oxidoreductase; EC 1.13.11.12) metabolites or autoxidation products was determined in vitro by estimation of 45Ca transport from a bulk aqueous to a bulk organic phase. Fresh commercial linoleic acid, tested immediately after removal from a sealed vial, stimulated calcium translocation only at concentrations greater than 1 mM. In contrast, 45Ca translocation by linoleic acid exposed to air was detectable at 10 microM. Oxidation products of linoleic acid obtained either by incubation with lipoxygenase or by autoxidation were much less potent than the calcium ionophore A23187. The products obtained by enzymic oxidation of linoleic acid enhanced contractility in the Langendorff-perfused guinea pig heart up to 45% over control (at 3 X 10(-8) M). The inotropic response was transient with rapid onset and not affected by the beta-adrenergic antagonist, propranolol. The autoxidation products of linoleic acid increased cardiac contractility up to 43% at 10(-6) M. In contrast, fresh linoleic acid caused only a negative inotropic effect at 10(-8) to 3 X 10(-7) M, progressing to contracture at 10(-6) M. These findings suggest that conflicting reports on the cardiostimulant effect of linoleic acid may be due to varying levels of the autoxidation products. Linoleic acid metabolites in vivo may have a physiological role in myocardial function related to their Ca2+-ionophoric activity.

Animals↗