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Department of Molecular Medicine, Northwest Hospital, Bothell, WA 98021
2To whom correspondence should be addressed. E-mail: Belury{at}u.washington.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONDietary CLA inhibits...CLA modulates cell proliferation...Effects of CLA on...LITERATURE CITED |
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KEY WORDS: • conjugated linoleic acid • carcinogenesis • CLA isomers • anticarcinogenic
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONDietary CLA inhibits...CLA modulates cell proliferation...Effects of CLA on...LITERATURE CITED |
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,2
). The double bonds of CLA may be in the positions of 7,9; 8,10; 9,11; 10,12; or 11,13 and the 3-dimensional geometric combinations of cis and/or trans configurations. The major isomers in foods are in the following rank order: c9t11-CLA (also called rumenic acid) > t7c9-CLA > 11,13-CLA (c/t) > 8,10-CLA (c/t) > t10c12-CLA isomer > other isomers (2
–4
). Importantly, the majority of experiments performed in experimental animals have used a synthetic mixture of CLA isomers containing primarily c9t11-CLA and t10c12-CLA (Fig. 1
) [reviewed in 5
)].
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–7
)]. In addition, CLA modulates immunity and thrombosis as well as fatty acid biochemistry, lipid metabolism and gene expression in the liver, muscle and adipose tissues (6
). There are several recent reviews on the effects and mechanisms of CLA in biological systems, including cancer (7
). Therefore, this review will focus on recently identified mechanisms by which CLA inhibits carcinogenesis. |
Dietary CLA inhibits carcinogenesis in experimental animals |
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TOPABSTRACTINTRODUCTIONDietary CLA inhibits...CLA modulates cell proliferation...Effects of CLA on...LITERATURE CITED |
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–10
). In addition, when a synthetic mixture of CLA isomers (
45% c9t11-CLA, 42% t10c12-CLA with several other remaining isomers comprising minor amounts) is provided in diets (0.5–1.5 g/100 g) either during or after initiation, chemically induced skin tumor promotion or mammary and colon tumorigenesis are inhibited (10
–13
). Furthermore, CLA inhibits the growth of transplanted cell lines derived from mammary (14
) and prostate (15
) cancers. Although the role of CLA in inhibiting carcinogenesis is convincing, not all studies have shown inhibition. In fact, CLA did not alter the growth of transplanted prostate (7
) and breast (16
) cancer cells and did not reduce tumorigenesis in an intestinal model of colon carcinogenesis using the ApcMin mouse (17
). No studies have yet reported that CLA enhances tumorigenesis.
In conjunction with identifying the inhibitory properties of CLA in various tumor models, efforts have been made to elucidate the role of CLA in modulating the stages of carcinogenesis known as initiation, promotion and progression. In particular, the anticarcinogenic property of CLA was first identified during the initiation stage of skin carcinogenesis, a stage associated with a genetic alteration in a subset of cells in the target tissue (8
). During initiation, CLA modulates events such as free radical–induced oxidation, carcinogen metabolism and carcinogen-DNA adduct formation in some tissues (7
). Findings have been ambiguous. In fact, a recent study in male rats demonstrated tissue-specific effects of CLA on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine–induced mutation frequencies (18
): Dietary CLA (0.5 g/100 g) reduced mutation frequency in the distal colon, but had no effect or enhanced mutation frequency in the proximal colon and cecum of rats.
In addition to tissue- and/or tumor model–specific effects of CLA on tumor initiation, several studies demonstrated that CLA inhibits carcinogenesis postinitiation (10
,11
,13
,19
,20
). In chemically induced mammary carcinogenesis, there may be an optimal time for exposure to CLA, i.e., the inhibitory properties of CLA on chemically induced mammary carcinogenesis were most profound when CLA was fed during mammary gland maturation [between 21 and 42 d of age (19
)]. During the promotion stage of skin carcinogenesis, CLA reduces the yield of mouse skin tumors by a mechanism distinct from its anti-initiator activity (10
).
Although a great deal of evidence demonstrates that dietary CLA inhibits the initiation and postinitiation and/or promotion stages of carcinogenesis, its role in the progression stage of carcinogenesis has not been established definitively. Using transplantable tumor models, dietary CLA reduced the growth rates of mammary and prostate cancer cells when implanted in vivo in mice (14
,15
). In addition, at least one study demonstrated that CLA (0.5–1.0 g/100 g) inhibited the ability of transplanted mammary cancer cells to form secondary tumors in mice (21
). Furthermore, the CLA-responsive chemically induced mammary carcinogenesis model (10
) is a model for human breast cancer ductal carcinomas in situ. Therefore, data showing that CLA inhibits tumorigenesis in this model are consistent with the possibility that CLA will reduce breast cancer metastasis. However, no studies have addressed the role of CLA in the prevention of metastatic cancer. It is critical to understand how CLA modulates malignant tumor formation and metastasis because the growth of secondary tumors is the major cause of morbidity and mortality in people with cancer.
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CLA modulates cell proliferation and apoptosis |
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TOPABSTRACTINTRODUCTIONDietary CLA inhibits...CLA modulates cell proliferation...Effects of CLA on...LITERATURE CITED |
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)]. In vivo, dietary CLA (1.0 g/100 g) reduces proliferation of terminal end bud and lobuloalveolar bud structures, the sites at which tumors form in both rat and human mammary cancers (22
). Furthermore, mammary adenocarcinomas induced by PhIP contained significantly fewer proliferating cell nuclear antigen positive cells in rats fed dietary CLA (0.1 g/100 g) compared with rats fed a control diet without CLA (13
). Recent work by Ip and colleagues (23
) demonstrated that CLA or c9t11-CLA–rich butter fat reduces the rate of incorporation of bromodeoxyuridine (BrdU) and the expression of cyclins A and D. These two cyclins regulate the conversion of G1 
S phase of the cell cycle (Fig. 2
). In addition, diets with CLA moderately increased levels of p16 and p27 proteins. These data suggest that CLA reduces cell proliferation by blocking DNA synthesis and cell cycle proteins that regulate this process (13
,23
). In contrast to findings in mammary carcinogenesis, dietary CLA does not reduce cell proliferation in phorbol ester–induced tumor promotion of mouse skin as measured by hyperplasia or ornithine decarboxylase activity, although c-myc mRNA was modestly reduced (24
). Furthermore, dietary CLA enhances cell proliferation and/or ornithine decarboxylase in livers of rats and mice (25
,26
).
|
. Dietary CLA induces apoptosis in numerous tissues including mammary gland (27
), liver (25
), colon (28
) and adipose (29
) tissues. In terminal end buds of rat mammary tissue initiated with methylnitrosurea, dietary CLA induces apoptosis in a site-specific manner. The ability of CLA to induce apoptosis in terminal end buds and the premalignant lesions known as intraductal proliferation lesions (27
) may have implications for development of this epithelial tissue. Induction of apoptosis by CLA was associated with reduction of Bcl-2 protein within the lesions. The Bcl-2 gene family has differential effects on apoptosis; for example, Bcl-2 and Bcl-xL suppress apoptosis, whereas others, such as Bax and Bak, promote apoptosis. The ability of Bax to induce apoptosis appears to involve a countereffect on Bcl-2. Although CLA reduced Bcl-2, there was only a moderate effect of CLA on induction of Bax protein. Therefore, it appears that CLA may support elevated apoptosis primarily by reducing the suppressor of apoptosis, bcl-2. Because the inhibitory effects of CLA or c9t11-CLA on reductions of BrdU incorporation in mammary epithelium were dependent on the proliferative (vs. quiescent) status of mammary epithelial cells (23
), effects of CLA on pivotal signaling events regulating both cell proliferation and apoptosis (e.g., cyclin dependent kinases or check point proteins such as p53) warrant further study. |
Effects of CLA on phospholipid metabolism and regulation of gene expression |
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TOPABSTRACTINTRODUCTIONDietary CLA inhibits...CLA modulates cell proliferation...Effects of CLA on...LITERATURE CITED |
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)]. Events in carcinogenesis that appear to be particularly sensitive to eicosanoids include cell proliferation, inflammation, local and systemic immunity, platelet aggregation and tissue differentiation. Diets with CLA result in an accumulation of CLA, especially the 9,11-CLA (c/t; t/c) isomer in phospholipids of tissues [e.g., liver (31
), mammary (32
), skin (24
) and others] and lipid fractions of human sera (M.A. Belury, unpublished data). In addition, when fed as the free fatty acid, dietary CLA alters the relative amounts of numerous other fatty acids in phospholipid fractions (24
,28
). These findings raise the possibility that CLA, when fed as the free fatty acid, competes with other fatty acids for incorporation into phospholipids and modifies subsequent eicosanoid production (especially from arachidonate, 20:4). In fact, dietary CLA reduces prostaglandin (PG)-E2 and/or other eicosanoids derived from enzymatic oxidation of arachidonic acid in some tissues (24
,28
). However, only one study has shown that dietary CLA reduces phospholipid-associated arachidonate (28
). In addition, when fed as triglyceride-esterified fatty acid (in CLA-rich butter), CLA does not alter phospholipid associated nonconjugated fatty acids (33
). Furthermore, some studies demonstrated that when dietary CLA altered the levels of nonconjugated fatty acids, these changes occurred in neutral lipid fractions of tissues [e.g., adipose (M.A. Belury, unpublished data), skin (24
), liver (31
) and mammary (32
). The relevance of reduced neutral lipid–associated arachidonate levels to altered arachidonate–derived eicosanoids is unclear at present.
Interestingly, when CLA lowers arachidonate-derived eicosanoids such as PGE2 and PGF2
in colon and skin (24
,28
), it also reduces tumorigenesis in these tissues. In contrast, at least one study has shown a relationship between an inability of dietary CLA to alter arachidonate-derived eicosanoids with a lack of its inhibition of intestinal tumorigenesis in Min mice (17
). Together, these studies indirectly suggest that the mechanism by which CLA inhibits carcinogenesis in some tissues may involve the modulation of arachidonate-derived eicosanoids.
CLA may reduce arachidonate-derived eicosanoids such as prostaglandin-E2, PGF2, leukotriene-B4 and leukotriene-C4 by one of two mechanisms. First, CLA may displace arachidonate incorporation into phospholipids as shown in cultured keratinocytes (34
). In addition, dietary CLA displaces the arachidonate precursor, linoleate, in a dose responsive manner in livers of mice fed various doses of CLA (0.5–1.5 g/100 g) in one study (31
) but not others (33
,35
Belury, M. A. unpublished data). A recent study demonstrated that dietary CLA reduces phospholipid-associated arachidonate in the colonic mucosa of rats (28
).
A second explanation for the reduction of arachidonate-derived eicosanoids by CLA may be through inhibition of the constitutive enzyme, cyclooxygenase (COX)-1, and/or the inducible form, COX-2, at the level of mRNA, protein, or activity. CLA or elongated and desaturated products from CLA (e.g., conjugated "arachidonate" or conjugated eicosatetraenoate) may act as antagonists for COX thereby reducing available enzyme (at the level of expression or activity) for arachidonate. Using an in vitro activity assay, CLA or individual isomers inhibited the rate of oxygenation of arachidonate in the presence of COX-1 (36
). Furthermore, c9t11-CLA and t10c12-CLA reduced COX-2 at the levels of mRNA and protein in a cultured macrophage cell line (37
).
Although CLA is readily metabolized by 
6 desaturase to form numerous downstream products (31
–33
,38
,39
), little is known about how CLA modulates metabolism of nonconjugated fatty acids via enzymatic systems such as 6 desaturase-elongase-5 desaturase. CLA reduces levels of linoleate (18:2) and its desaturated and elongated product, arachidonate (20:4) in mammary tissue (32
). In contrast, one study has shown that CLA may modestly enhance levels of neutral lipid–associated arachidonate in the epidermis of mice (24
). Furthermore, other studies showed no effect of CLA on arachidonate levels in fat pads (40
), liver (33
) or small intestine (17
). The ability of CLA to alter arachidonate levels may depend on the form of CLA (free fatty acid vs. esterified) as well as tissue- and species-specific effects. The relevance of altered arachidonate levels in neutral lipids vs. phospholipid as a modulator of lipid metabolism and eicosanoid formation is not clear at the present time.
CLA may modulate lipid metabolism in part by a mechanism dependent on the activation of the nuclear hormone receptors, peroxisome proliferator-activated receptors (PPAR) [reviewed in (5
)]. In particular, the PPAR
isoform is found in extrahepatic tissues such as adipose, prostate, colon, mammary gland and others. PPAR2 is a required transcription factor in adipose tissue differentiation [reviewed in (41
)]. In addition, thiazolidinediones, high affinity ligands for PPAR, modulate carcinogenesis in mammary gland, colon and prostate tissues [reviewed in (42
)]. Isomers of CLA have moderate affinity for binding to and activating PPAR (43
). Dietary CLA appears to modulate transcription of genes responsive to PPAR in adipose tissue in vivo [reviewed in (6
)] and in vitro (37
). Our current attempts to study the ability of CLA to activate PPAR have focused on downstream metabolites of 6 desaturase metabolism of c9t11-CLA or t10c12-CLA. In these studies, we have used approaches to block desaturase activity to determine whether reducing metabolites alters activation of PPAR (43
). CV-1 cells were transiently transfected with murine PPAR, luciferase-peroxisome proliferator responsive element reporter and ß-galactosidase, and treated with c9t11-CLA or t10c12-CLA. The activation of PPAR was determined by measuring luciferase activity. By blocking 6 desaturase using the synthetic inhibitor, SC-26196 (44
), the ability of CLA isomers to activate PPAR was reduced (P < 0.05). These data indirectly suggest that activation of PPAR by CLA is increased by the formation of the 6-desaturated products from CLA, c6c9t11-CLA or c6t10c12-CLA. However, the activation of PPAR by these products is yet to be measured.
In addition to evidence showing that CLA may induce PPAR-responsive genes in vivo, CLA may induce the level of PPAR itself (45
). Because PPAR2 is thought to be one of several transcription factors required for adipose tissue differentiation (41
), and because new evidence suggests that activators of PPAR are protective against cancers arising in the mammary gland, colon and prostate (42
), it is possible that some of the molecular mechanisms of action of CLA on carcinogenesis are mediated by PPAR. Perhaps the ability of PPAR to mediate effects of CLA is through increased levels of PPAR protein (45
) and/or through activation of PPAR by downstream metabolites of CLA [e.g., desaturase and elongase products (43
)].
In summary, an inverse relationship has been observed between CLA accumulation and outcomes of breast cancer in postmenopausal women (46
). However, a preventive role for CLA in human cancer (breast and possibly others) is still unproven. To date, all intervention studies have been conducted in experimental animal models of carcinogenesis. It has been estimated that dietary factors contribute to approximately one third of deaths due to cancer in the United States (47
). Because CLA inhibits carcinogenesis in numerous animal models and at multiple stages, this group of fatty acids offers the possibility that several types of cancers in humans may be prevented with a diet rich in a diversity of chemopreventive compounds, including CLA. More work is required to understand fully the implications of dietary CLA and the possibility of lowering the risk for human cancer development.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: BrdU, bromodeoxyuridine; CLA, conjugated linoleic acid; COX, cyclooxygenase; PG, prostaglandin; PPAR, peroxisome proliferator-activated receptors.
Manuscript received 16 July 2002. Revision accepted 18 July 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONDietary CLA inhibits...CLA modulates cell proliferation...Effects of CLA on...LITERATURE CITED |
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1. Chin, S. F., Liu, W., Storkson, J. M., Ha, Y. L. & Pariza, M. W. (1992) Dietary sources of conjugated dienoic isomers of linoleic acid, a newly recognized class of anticarcinogens. J. Food Compos. Anal. 5:185-197.
2. Ma, D., Wierzbicki, A., Field, C. & Clandinin, M. T. (1999) Conjugated linoleic acid in Canadian dairy and beef products. J. Agric. Food Chem. 47:1956-1960.[Medline]
3. Fritsche, J., Rickert, R. & Steinhart, H. (1999) Formation, contents, and estimation of daily intake of conjugated linoleic acid isomers and trans-fatty acids in foods. Yurawecz, M. P. Mossoba, M. M. Kramer, J.K.G. Pariza, M. W. Nelson, G. J. eds. Advances in Conjugated Linoleic Acid Research Vol. 1:378-396 AOCS Press Champaign, IL. .
4. Kramer, J.K.G., Parodi, P. W., Jensen, R. G., Mossoba, M. M., Yurawecz, M. P. & Adlof, R. O. (1998) Rumenic acid: a proposed common name for the major conjugated linoleic acid isomer found in natural products [letter]. Lipids 33:835.[Medline]
5. Belury, M. A. & Vanden Heuvel, J. P. (1997) Protection against cancer and heart disease by CLA: potential mechanisms of action. Nutr. Disease Update 1:58-63.
6. Belury, M. A. (2002) Dietary conjugated linoleic acid in health: physiological effects and mechanisms of action. Annu. Rev. Nutr. 22:505-531.[Medline]
7. Scimeca, J. A. (1999) Cancer inhibition in animals. Yurawecz, M. P. Mossobo, M. M. Kramer, J.K.G. Pariza, M. W. Nelson, G. J. eds. Advances in Conjugated Linoleic Acid Research Vol. 1:420-443 AOCS Press Champaign, IL. .
8. Ha, Y. L., Grimm, N. K. & Pariza, M. W. (1987) Anticarcinogens from fried ground beef heat-altered derivatives of linoleic acid. Carcinogenesis 8:1881-1887.
9. Ha, Y. L., Storkson, J. M. & Pariza, M. W. (1990) Inhibition of benzo(a)pyrene-induced mouse forestomach neoplasia by conjugated dienoic derivatives of linoleic acid. Cancer Res. 50:1097-1101.
10. Ip, C., Chin, S. F., Scimeca, J. A. & Pariza, M. W. (1991) Mammary cancer prevention by conjugated dienoic derivative of linoleic acid. Cancer Res. 51:6118-6124.
11. Belury, M. A., Nickel, K., Bird, C. E. & Wu, Y. (1996) Dietary conjugated linoleic acid modulation of phorbol ester skin tumor promotion. Nutr. Cancer 26:149-157.[Medline]
12. Liew, C., Schut, H.A.J., Chin, S. F., Pariza, M. W. & Dashwood, R. H. (1995) Protection of conjugated linoleic acid against 2-amino-3-methylimidazol[4,5-f]quinoline-induced colon carcinogenesis in the F344 rat: a study of inhibitory mechanisms. Carcinogenesis 16:3037-3043.
13. Futakuchi, M., Cheng, J. L., Hirose, M., Kimoto, N., Cho, Y.-M., Iwata, T., Kasai, M., Tokudome, S. & Shirai, T. (2002) Inhibition of conjugated fatty acids derived from safflower or perilla oil of induction and development of mammary tumors in rats induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Cancer Lett 178:131-139.[Medline]
14. Visonneau, S., Cesano, A., Tepper, S. A., Scimeca, J. A., Santoli, D. & Kritchevsky, D. (1997) Conjugated linoleic acid suppresses the growth of human breast adenocarcinoma cells in SCID mice. Anticancer Res. 17:969-974.[Medline]
15. Cesano, A., Visonneau, S., Scimeca, J. A., Kritchevsky, D. & Santoli, D. (1998) Opposite effects of linolenic acid and conjugated linoleic acid on human prostatic cancer in SCID mice. Anticancer Res. 18:833-838.[Medline]
16. Wong, M. W., Chew, B. P., Wong, T. S., Hosick, H. L., Boylston, T. D. & Shultz, T. D. (1997) Effects of dietary conjugated linoleic acid on lymphocyte function and growth of mammary tumors in mice. Anticancer Res. 17:987-994.[Medline]
17. Petrick, M.B.H., McEntee, M. F., Johnson, B. T., Obukowicz, M. G. & Whelan, J. (2000) Highly unsaturated (n-3) fatty acids, but not -linolenic, conjugated linoleic or -linolenic acids, reduce tumorigenesis in APCMin/+ mice. J. Nutr. 130:2434-2443.
18. Yang, H., Glickman, B. W. & de Boer, J. G. (2001) Effect of conjugated linoleic acid on the formation of spontaneous and PhIP-induced mutation in the colon and cecum of rats. Mutat. Res. 9292:1-12.
19. Ip, C., Scimeca, J. A. & Thompson, H. J. (1995) Effect of timing and duration of dietary conjugated linoleic acid on mammary cancer prevention. Nutr. Cancer 24:241-247.[Medline]
20. Ip, C., Jiang, C., Thompson, H. J. & Scimeca, J. A. (1997) Retention of conjugated linoleic acid in the mammary gland is associated with tumor inhibition during the post-initiation phase of carcinogenesis. Carcinogenesis 18:755-759.
21. Hubbard, N. E., Lim, D., Summers, L. & Ericson, K. L. (2000) Reduction of murine mammary tumor metastasis by conjugated linoleic acid. Cancer Lett 150:93-100.[Medline]
22. Thompson, H., Zhu, Z., Banni, S., Darcy, K., Loftus, T. & Ip, C. (1997) Morphological and biochemical status of the mammary gland as influenced by conjugated linoleic acid: implication for a reduction in mammary cancer risk. Cancer Res. 57:5067-5072.
23. Ip, C., Dong, Y., Thompson, H. J., Bauman, D. E. & Ip, M. M. (2001) Control of rat mammary epithelium proliferation by conjugated linoleic acid. Nutr. Cancer 39:233-238.[Medline]
24. Kavanaugh, C. J., Liu, K. L. & Belury, M. A. (1999) Effect of dietary conjugated linoleic acid on phorbol ester-induced PGE2 production and hyperplasia in mouse epidermis. Nutr. Cancer 33:132-138.[Medline]
25. Lu, M., Gottschling, B., Kamendulis, L., Klaunig, J. E. & Belury, M. A. (2000) Dietary CLA induces hepatocyte proliferation in F33 rats. FASEB J. 14:A721.
26. Belury, M. A., Moya-Camarena, S. Y., Liu, K.-L. & Vanden Heuvel, J. P. (1997) Conjugated linoleic acid induces peroxisome proliferator-associated enzyme expression and ornithine decarboxylase activity in mouse liver. J. Nutr. Biochem. 8:579-584.
27. Ip, C., Ip, M. M., Loftus, T., Shoemaker, S. F. & Shea-Eaton, W. (2000) Induction of apoptosis by conjugated linoleic acid in cultured mammary tumor cells and premalignant lesions of the rat mammary gland. Cancer Epidemiol. Biomarkers Prev. 9:689-696.
28. Park, H. S., Ryu, J. H., Ha, Y. L. & Park, J.H.Y. (2001) Dietary conjugated linoleic acid (CLA) induces apoptosis of colonic mucosa in 1,2-dimethylhydrazine-treated rats: a possible mechanism of the anticarcinogenic effect of CLA. Br. J. Nutr. 86:549-555.[Medline]
29. Tsuboyama-Kasaoka, N., Takahashi, M., Tanemura, K., Kim, H.-J., Tange, T., Okuyama, H., Kasai, M., Ikemoto, S. & Ezaki, O. (2000) Conjugated linoleic acid supplementation reduces adipose tissue by apoptosis and develops lipodystrophy in mice. Diabetes 49:1534-1542.[Abstract]
30. Fischer, S. M. (1995) Eicosanoids and tumor promotion. Mukhtar, H. eds. Skin Cancer: Mechanisms and Human Relevance 1995:129-143 CRC Press Boca Raton, FL. .
31. Belury, M. A. & Kempa-Steczko, A. (1997) Conjugated linoleic acid modulates hepatic lipid composition in mice. Lipids 32:199-204.[Medline]
32. Banni, S., Angioni, E., Casu, V., Melis, M., Carta, G., Corongiu, F., Thompson, H. & Ip, C. (1999) Decrease in linoleic acid metabolites as a potential mechanism in cancer risk reduction by conjugated linoleic acid. Carcinogenesis 20:1019-1024.
33. Moya-Camarena, S. Y., Vanden Heuvel, J. P. & Belury, M. A. (1999) Conjugated linoleic acid activates peroxisome proliferator-activated receptor and ß subtypes but does not induce hepatic peroxisome proliferation in Sprague-Dawley rats. Biochim. Biophys. Acta 1436:331-342.[Medline]
34. Banni, S., Carta, G., Angioni, E., Murru, E., Scanu, P., Melis, M. P., Bauman, D. E., Fischer, S. M. & Ip, C. (2001) Distribution of conjugated linoleic acid and metabolites in different lipid fractions in the rat liver. J. Lipid Res. 42:1056-1061.
35. Liu, K. L. & Belury, M. A. (1998) Conjugated linoleic acid reduces arachidonic acid content and PGE2 synthesis in murine keratinocytes. Cancer Lett 124:1-8.[Medline]
36. Bulgarella, J., Patton, D. & Bull, A. (2001) Modulation of prostaglandin H synthase activity by conjugated linoleic acid (CLA) and specific CLA isomers. Lipids 36:407-412.[Medline]
37. Yu, Y., Correll, P. H. & Vanden Heuvel, J. P. (2002) Conjugated linoleic acid decreases production of pro-inflammatory products in macrophages: evidence for a PPAR-dependent mechanism. Biochim. Biophys. Acta (in press).
38. Banni, S., Day, B. W., Evans, R. W., Corongiu, F. P. & Lombardi, B. (1995) Detection of conjugated diene isomers of linoleic acid in liver lipids of rats fed a choline-devoid diet indicates that the diet does not cause lipoperoxidation. J. Nutr. Biochem. 6:281-289.
39. Sébédio, J.-L., Juanéda, P., Dobson, G., Ramilison, I., Martin, J. C., Chardigny, J. M. & Christie, W. W. (1997) Metabolites of conjugated isomers of linoleic acid (CLA) in the rat. Biochim. Biophys. Acta 1345:5-10.[Medline]
40. Sisk, M., Hausman, D., Martin, R. & Azain, M. (2001) Dietary conjugated linoleic acid reduces adiposity in lean but not obese Zucker rats. J. Nutr. 131:1668-1674.
41. Ntambi, J. M. & Kim, Y.-C. (2000) Adipocyte differentiation and gene expression. J. Nutr. 130:3122S-3126S.
42. Sporn, M. B., Suh, N. & Mangelsdorf, D. J. (2001) Prospects for prevention and treatment if cancer with selective PPAR-gamma modulators (SPARMS). Trends Mol. Med. 7:395-400.[Medline]
43. Belury, M. A., Moya-Camarena, S. Y., Lu, M., Shi, L., Leesnitzer, L. M. & Blanchard, S. G. (2002) Conjugated linoleic acid is an activator and ligand for peroxisome proliferator-activated receptor- (PPAR). Nutr. Res. 22:817-824.
44. Obukowicz, M. G., Raz, A., Pyla, P. D., Rico, J. G., Wendling, J. M. & Needleman, P. (1998) Identification and characterization of a novel 6/5 fatty acid desaturase inhibitor as a potential anti-inflammatory agent. Biochem. Pharm. 55:1045-1058.[Medline]
45. Evans, M., Pariza, M., Park, Y., Curtis, L., Kuebler, B. & McIntosh, M. (2000) Trans-10cis-12 conjugated linoleic acid reduces triglyceride content while differentially affecting peroxisome proliferator activated receptor-2 and aP2 expression in 3T3–L1 preadipocytes. Lipids 36:1223-1232.
46. Aro, A., Mannisto, S., Salminen, I., Ovaskainen, M.-L., Kataja, V. & Uusitupa, M. (2000) Inverse association between dietary and serum conjugated linoleic acid and risk of breast cancer in postmenopausal women. Nutr. Cancer 38:151-157.[Medline]
47. Peto, R., Roe, F.J.C., Lee, P. N., Levy, L. & Clack, J. (1975) Cancer and ageing in mice and men. Br. J. Cancer 32:411-426.[Medline]
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 L. M. Rodriguez-Alcala and J. Fontecha Hot Topic: Fatty Acid and Conjugated Linoleic Acid (CLA) Isomer Composition of Commercial CLA-Fortified Dairy Products: Evaluation After Processing and Storage J Dairy Sci, May 1, 2007; 90(5): 2083 - 2090. [Abstract] [Full Text] [PDF]
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 E. Barrett, R. P. Ross, G. F. Fitzgerald, and C. Stanton Rapid Screening Method for Analyzing the Conjugated Linoleic Acid Production Capabilities of Bacterial Cultures Appl. Envir. Microbiol., April 1, 2007; 73(7): 2333 - 2337. [Abstract] [Full Text] [PDF]
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 S. Chen, S.-R. Oh, S. Phung, G. Hur, J. J. Ye, S. L. Kwok, G. E. Shrode, M. Belury, L. S. Adams, and D. Williams Anti-Aromatase Activity of Phytochemicals in White Button Mushrooms (Agaricus bisporus) Cancer Res., December 15, 2006; 66(24): 12026 - 12034. [Abstract] [Full Text] [PDF]
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 A. Ferramosca, V. Savy, L. Conte, S. Colombo, A. W. C. Einerhand, and V. Zara Conjugated linoleic acid and hepatic lipogenesis in mouse: role of the mitochondrial citrate carrier J. Lipid Res., September 1, 2006; 47(9): 1994 - 2003. [Abstract] [Full Text] [PDF]
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J. B. Ewaschuk, J. W. Walker, H. Diaz, and K. L. Madsen Bioproduction of Conjugated Linoleic Acid by Probiotic Bacteria Occurs In Vitro and In Vivo in Mice J. Nutr., June 1, 2006; 136(6): 1483 - 1487. [Abstract] [Full Text] [PDF]
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H. J. Cho, E. J. Kim, S. S. Lim, M. K. Kim, M.-K. Sung, J.-S. Kim, and J. H. Y. Park Trans-10,cis-12, Not cis-9,trans-11, Conjugated Linoleic Acid Inhibits G1-S Progression in HT-29 Human Colon Cancer Cells J. Nutr., April 1, 2006; 136(4): 893 - 898. [Abstract] [Full Text] [PDF]
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C. Corino, A. Di Giancamillo, R. Rossi, and C. Domeneghini Dietary Conjugated Linoleic Acid Affects Morphofunctional and Chemical Aspects of Subcutaneous Adipose Tissue in Heavy Pigs J. Nutr., June 1, 2005; 135(6): 1444 - 1450. [Abstract] [Full Text] [PDF]
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 R. L. House, J. P. Cassady, E. J. Eisen, T. E. Eling, J. B. Collins, S. F. Grissom, and J. Odle Functional genomic characterization of delipidation elicited by trans-10, cis-12-conjugated linoleic acid (t10c12-CLA) in a polygenic obese line of mice Physiol Genomics, May 11, 2005; 21(3): 351 - 361. [Abstract] [Full Text] [PDF]
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S. Chung, J. M. Brown, M. B. Sandberg, and M. McIntosh Trans-10,cis-12 CLA increases adipocyte lipolysis and alters lipid droplet-associated proteins: role of mTOR and ERK signaling J. Lipid Res., May 1, 2005; 46(5): 885 - 895. [Abstract] [Full Text] [PDF]
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A. Bhattacharya, Md. M. Rahman, D. Sun, R. Lawrence, W. Mejia, R. McCarter, M. O'Shea, and G. Fernandes The Combination of Dietary Conjugated Linoleic Acid and Treadmill Exercise Lowers Gain in Body Fat Mass and Enhances Lean Body Mass in High Fat-Fed Male Balb/C Mice J. Nutr., May 1, 2005; 135(5): 1124 - 1130. [Abstract] [Full Text] [PDF]
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E. Castaneda-Gutierrez, T. R. Overton, W. R. Butler, and D. E. Bauman Dietary Supplements of Two Doses of Calcium Salts of Conjugated Linoleic Acid During the Transition Period and Early Lactation J Dairy Sci, March 1, 2005; 88(3): 1078 - 1089. [Abstract] [Full Text] [PDF]
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 J. M. Brown, M. S. Boysen, S. Chung, O. Fabiyi, R. F. Morrison, S. Mandrup, and M. K. McIntosh Conjugated Linoleic Acid Induces Human Adipocyte Delipidation: AUTOCRINE/PARACRINE REGULATION OF MEK/ERK SIGNALING BY ADIPOCYTOKINES J. Biol. Chem., June 18, 2004; 279(25): 26735 - 26747. [Abstract] [Full Text] [PDF]
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C. J Field and P. D Schley Evidence for potential mechanisms for the effect of conjugated linoleic acid on tumor metabolism and immune function: lessons from n-3 fatty acids Am. J. Clinical Nutrition, June 1, 2004; 79(6): 1190S - 1198S. [Abstract] [Full Text] [PDF]
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G. C. Burdge, B. Lupoli, J. J. Russell, S. Tricon, S. Kew, T. Banerjee, K. J. Shingfield, D. E. Beever, R. F. Grimble, C. M. Williams, et al. Incorporation of cis-9,trans-11 or trans-10,cis-12 conjugated linoleic acid into plasma and cellular lipids in healthy men J. Lipid Res., April 1, 2004; 45(4): 736 - 741. [Abstract] [Full Text] [PDF]
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P. A. Masso-Welch, D. Zangani, C. Ip, M. M. Vaughan, S. F. Shoemaker, S. O. McGee, and M. M. Ip Isomers of Conjugated Linoleic Acid Differ in Their Effects on Angiogenesis and Survival of Mouse Mammary Adipose Vasculature J. Nutr., February 1, 2004; 134(2): 299 - 307. [Abstract] [Full Text] [PDF]
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K. Eder, S. Schleser, K. Becker, and R. Korting Conjugated Linoleic Acids Lower the Release of Eicosanoids and Nitric Oxide from Human Aortic Endothelial Cells J. Nutr., December 1, 2003; 133(12): 4083 - 4089. [Abstract] [Full Text] [PDF]
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M. Q. Kemp, B. D. Jeffy, and D. F. Romagnolo Conjugated Linoleic Acid Inhibits Cell Proliferation through a p53-Dependent Mechanism: Effects on the Expression of G1-Restriction Points in Breast and Colon Cancer Cells J. Nutr., November 1, 2003; 133(11): 3670 - 3677. [Abstract] [Full Text] [PDF]
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J. A. Milner Incorporating Basic Nutrition Science into Health Interventions for Cancer Prevention J. Nutr., November 1, 2003; 133(11): 3820S - 3826. [Abstract] [Full Text] [PDF]
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J. M. Brown and M. K. McIntosh Conjugated Linoleic Acid in Humans: Regulation of Adiposity and Insulin Sensitivity J. Nutr., October 1, 2003; 133(10): 3041 - 3046. [Abstract] [Full Text] [PDF]
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E. J. Kim, I.-J. Kang, H. J. Cho, W. K. Kim, Y.-L. Ha, and J. H. Y. Park Conjugated Linoleic Acid Downregulates Insulin-Like Growth Factor-I Receptor Levels in HT-29 Human Colon Cancer Cells J. Nutr., August 1, 2003; 133(8): 2675 - 2681. [Abstract] [Full Text] [PDF]
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): significant (P < 0.05); dotted lines (······): modest (P < 0.05). Abbreviation: cdk, cyclin-dependent kinase.