Progress 09/30/99 to 10/01/04
Outputs
Dietary factors are predicted to affect up to 35% of all cancers. In particular, types of dietary fat may have protective or enhancing effects on cancer risk. The hypothesis of our laboratory is that a group of fatty acids, collectively known as conjugated linoleate (CLA), are protective against mammary and skin cancers via activation of peroxisome proliferator-activated receptors (PPARs). We have recently found that some CLA isomers are high affinity ligands and activators for PPARalpha. We also recently identified that CLA induces PPAR-responsive genes in liver and in cultured cells.
Impacts
The finding that CLA may work, at least in part, via activation of a nuclear receptor will be useful in identifying isomers that are effective against cancer. In addition, understanding molecular mechanisms is useful in predicting optimal doses of CLA that will be chemoprotective.
Publications
- No publications reported this period
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Progress 10/01/98 to 09/30/99
Outputs
Dietary factors are predicted to affect up to 35% of all cancers. In particular, types of dietary fat may have protective or enhancing effects on cancer risk. The hypothesis of our laboratory is that a group of fatty acids, collectively known as conjugated linoleate (CLA), are protective against mammary and skin cancers via activation of peroxisome proliferator-activated receptors (PPARs). We have recently found that some CLA isomers are high affinity ligands and activators for PPARalpha. We also recently identified that CLA induces PPAR-responsive genes in liver and in cultured cells.
Impacts
The finding that CLA may work, at least in part, via activation of a nuclear receptor will be useful in identifying isomers that are effective against cancer. In addition, understanding molecular mechanisms is useful in predicting optimal doses of CLA that will be chemoprotective.
Publications
- Belury, MA, Moya-Camarena, SY, Sun, H, Snyder, E, Davis, II, JW, Cunningham, ML, Vanden Heuvel, JP. Peroxisome proliferator-dependent gene regulation: examination of dose response relationships by quanititative reverse transcritpase -polymerase chain reaction. Toxicol. Appl. Pharmacol 151:254-261, 1998.
- Belury, MA. Introduction for Symposium, Steroid Hormone Receptor and Nutrient Interactions: Implications for Cancer Prevention. J. Nutr 129: 569s-570s, 1999.
- Moya-Camarena, SY, Vanden Heuvel, JP, Belury, MA. Conjugated linoleic acid activates peroxisome proliferator-activated receptor subtypes but does not induce peroxisome proliferation in Sprague Dawley rats. Biochim Biophys Acta, 1436: 331-342, 1999.
- Kavanaugh, CJ, Liu, K-L, Belury, MA. Effect of dietary conjugated linoleic acid on phorbol ester induced PGE2 production and hyperplasia. Nutr Cancer 33: 132-138, 1999.
- Belury, MA and Vanden Heuvel, JP. Modulation of Diabetes by Conjugated Linoleic Acid. Invited review chapter In: "Conjugated linoleic acid: Biochemical, nutritional, clinical and methodological aspects," eds: Yurawecz, MP, Mossoba, MM, Kramer, JKG, Nelson, G and Pariza, MW. Am Oil Chem Soc Press, Campaign IL; pp. 404-411; 1999.
- Nickel, KP, Belury, MA. Inositol hexaphosphate reduces 12-0-tetradecanoylphorbol-13-acetate-induced ornithine decarboxylase independent of protein kinase C isoform expression in keratinocytes. Cancer Lett. 140: 105-111, 1999.
- Moya-Camarena, SY, Vanden Heuvel, JP, Blanchard, SG, Belury, MA. Conjugated linoleic acid is a high affinity, naturally occurring ligand that activates PPAR. J Lipid Res. 40: 1426-1433, 1999.
- Moya-Camarena, SY, Belury, MA. Conjugated linoleic acids modulate hepatic lipid metabolism and gene expression in rodents. Invited Review: Nutr Rev 57: 337-341, 1999.
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Progress 10/01/97 to 09/30/98
Outputs
Conjugated linoleic acid (CLA) inhibits mouse skin carcinogenesis. Recently our laboratory has shown that CLA is a ligand of the peroxisome proliferator-activated receptor (PPAR) and CLA induces PPAR-responsive gene expression in the rodent liver. In mouse epidermis and a murine keratinocyte cell line (HEL-30), all three isoforms of PPAR were expressed with the following levels of abundance: PPAR-alpha > PPAR-beta > PPAR-gamma. Moreover, the amount of PPAR-beta mRNA was significantly elevated in papillomas and carcinomas compared to normal mouse epidermis (p<0.05). We hypothesize CLA inhibits mouse skin tumor promotion through a PPAR-beta mediated mechanism. Female mice (CD-1) were fed diets containing different amounts of CLA (0.0%, 0.5%, 1.0% and 1.5% by wt) for 6 weeks and then topically treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) or acetone for 6 hours. PPAR-beta mRNA expression was significantly induced by TPA compared with acetone treatment (p<0.05).
However dietary CLA decreased TPA-induced PPAR-beta mRNA expression compared with the control group (fed 0.0% CLA). In addition, CLA decreased TPA induced PPAR-beta expression in cultured keratinocytes. A putative PPAR-responsive gene, keratinocyte fatty acid binding protein (KLBP) was overexpressed in mouse skin papillomas and carcinomas (at least 10 fold induction) compared to levels in normal epidermis. Further, KLPB mRNA expression was elevated in TPA-treated mouse epidermis compared with acetone treated mice. The fact that CLA modulates TPA-induced PPAR-beta and KLBP mRNA expression may begin to explain the mechanisms of CLA inhibition of tumorigenesis.
Impacts
(N/A)
Publications
- 25. Belury, MA, Moya-Camarena, SY, Sun, H, Snyder, E, Davis, II, JW, Cunningham, ML, Vanden Heuvel, JP. Peroxisome proliferator-dependent gene regulation: examination of dose response relationships by quanititative reverse transcritpase polymerase chain reaction. Toxicol. Appl. Pharmacol 151, 254-261, 1998. 27. Moya-Camarena, SY, Vanden Heuvel, JP, Belury, MA. Conjugated linoleic acid activates peroxisome proliferator activated receptor alpha and beta subtypes but does not induce peroxisome proliferation in Sprague Dawley rats. Biochim Biophys Acta, in press, 1999. 26. Belury, MA. Introduction for Symposium, Steroid Hormone Receptor and Nutrient Interactions: Implications for Cancer Prevention. J. Nutr. in press, 1999. 28. Kavanaugh, CJ, Liu, KL, Belury, MA. Effect of dietary conjugated linoleic acid on phorbol ester induced PGE2 production and hyperplasia. Nutr Cancer, in press, 1999.
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Progress 10/01/96 to 09/30/97
Outputs
An objective in my laboratory is to determine the role of dietary conjugated linoleic acid (CLA) in cancer. In previous studies we have shown that the dietary fatty acid, CLA, inhibits phorbol ester-induced skin tumor promotion in mice. In addition, we have shown that CLA is incorporated into phospholipids of cultured murine keratinocytes in a dose-dependent manner. Fatty acid derived-prostaglandins are known to play a role in the inflammatory process associated with carcinogenesis. Therefore, we hypothesize that the chemoprotective effects of CLA in mouse epidermis occur, in part, via dietary manipulation of phospholipid fatty acid composition and altered prostaglandin production. Female CD-1 mice were fed semi-purified diets containing 0.0%, 0.5%, 1.0%, or 1.5% CLA (by weight) for six weeks. Increasing levels of dietary CLA resulted in significantly elevated (p<0.05) levels of 9,11- and 10,12-CLA isomers in neutral and phospholipids of mouse epidermis as measured by
gas chromatography. The levels of palmitoleate (16:1) and linoleate (18:2) were significantly reduced (p<0.05) in phospholipids of mice fed increasing levels of dietary CLA while palmitate (16:0) and stearate (18:0) were significantly elevated (p<0.05). Mice fed 1.5% dietary CLA exhibited significantly lower levels of PGE2 (p<0.05); however, lower levels of dietary CLA (0.0%, 0.5% or 1.0%) had no effect on PGE2 levels. Phorbol ester-induced ornithine decarboxylase activity, an event associated with hyperproliferative cells and tumor promotion, was unaltered by dietary CLA. These data support the hypothesis that CLA inhibits TPA-induced tumor promotion via a mechanism involving modulation of PGE2 synthesis. In a separate group of experiments we have utilized cultured epidermal cells to determine the mechanisms of how CLA exerts its potent chemoprotective effects. In these studies, it was shown that CLA treatment induces the expression of a gene known as acyl CoA oxidase (ACO). The
transcription of the ACO gene is thought to be regulated, in part, by peroxisome proliferator-activated receptors since the enhancer region of ACO contains responsive elements for this transcription factor. In addition, it is interesting to note that ACO is associated with carcinogenesis properties such as apoptosis in the liver; however, the implications of CLA induction of ACO expression in epidermal carcinogenesis are not yet known.
Impacts
(N/A)
Publications
- Publications: (6) Liu, KL, Belury, MA. Effect of linoleic and conjugated linoleic acids on arachidonate-derived PGE2 and biological activity in mouse eratinocytes. Cancer Lett., in press, 1997.
- Belury, MA, Moya-Camarena, SY, Liu, KL, Vanden Heuvel, JP. Conjugated linoleic acid induces peroxisome proliferator-associated enzyme expression and ornithine decarboxylase activity in mouse liver. J. Nutr. Biochem:, 8: 579-584, 1997.
- Liu, KL, Belury, MA. Incorporation and biological activity of conjugated linoleic acid in mouse keratinocytes. Lipids 32:725-730, 1997.
- Belury, MA, Kempa-Steczko, A. Dietary conjugated linoleic acid modulates hepatic lipid composition in mice. Lipids, 32: 199-204, 1997.
- Nickel, KP, Nielsen, SS, Smart, D, Mitchell, CA, Belury, MA. Calcium bioavailability of vegan diets for a bioregenerative life support system. J. Food Sci., 62: 619-621, 1997.
- Belury, MA, Vanden Heuvel, JP. Invited Review; Protection against cancer and heart disease by the dietary fat, conjugated linoleic acid: potential mechanisms of action. Nutr. Disease Update Journal 1: 58-63, 1997.
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Progress 10/01/95 to 09/30/96
Outputs
The fatty acid, conjugated linoleic acid (CLA), has been shown to inhibit mouse skin tumor promotion. Because little is known about the metabolic fate of this fatty acid derivative, we are currently investigating the role of CLA in fatty acid metabolism in cultured epidermal and hepatic cells as well as rodent epidermis and liver. To evaluate whether CLA was able to be incorporated into keratinocytes, the uptake of 14C-conjugated linoleic acid (CLA) was compared to the incorporation of 14C-linoleic acid (LA) and 14C-arachidonic acid (AA) over time. Incorporation of the fatty acids was maximal by 12 hr. and approximately 85-90% exogenous radiolabeled fatty acid was incorporated into cells by 24 hr. Incorporation of 14C-CLA into keratinocytes was slightly lower compared to uptake of 14C-LA or 14C-AA. The incorporation of 14C-LA and 14C-CLA into phospholipid fractions was different than 14C-AA distribution but similar to each other: The majority (57%) of 14C-LA or
14C-CLA was incorporated into phosphatidylcholine with phosphatidylethanolamine and phosphatidylserine/ phosphatidylinositol contained 15%-27% of 14C-LA or 14C-CLA. Treatment of cultured keratinocytes with phorbol ester tumor promoter resulted in significantly reduced levels of prostaglandin E2 in CLA pre-treated cultures compared to cultures pre-treated with linoleate or arachidonate. Furthermore, phorbol ester treatment was also reduced in cultures pre-treated with CLA compared to linoleate or arachidonate. These data suggest that che.
Impacts
(N/A)
Publications
- Belury, MA, Vanden Heuvel, JP. Protection against cancer and heart disease by the dietary fat, conjugated linoleic acid: potential mechanisms of action. Nutr Disease Update Journal, in press, 1997.
- Belury, MA, Bird, C, Nickel, KP, Wu, B. Inhibition of mouse skin tumor promotion by dietary conjugated linoleate, Nutr Cancer, 26: 149-157, 1996.
- Belury, MA, Moya-Camarena, SM, Liu, K-L, Vanden Heuvel, JP. Conjugated linoleic acid induces peroxisome proliferation-associated events and ornithine decarboxylase activity in mouse liver.
- Belury, MA, Kempa-Steczko, A. Dietary conjugated linoleic acid modulates hepatic lipid composition in mice.
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Progress 01/01/95 to 12/30/95
Outputs
The fatty acid, conjugated linoleic acid (CLA), has been shown to inhibit mouse skin tumor promotion. Because little is known about the metabolic fate of this fatty acid derivative, we are currently investigating the role of CLA in fatty acid metabolism in cultured keratinocytes. To evaluate whether CLA was able to be incorporated into keratinocytes, the uptake of (superscript 14)C-conjugated linoleic acid (CLA) was compared to the incorporation of (superscript 14)C-linoleic acid (LA) and (superscript 14)C-arachidonic acid (AA) over time. The mouse keratinocyte cell line, HEL-30 was grown in serum free media, 0.1% albumin and 0.1mCi/ml (superscript 14)C-fatty acid (LA, CLA or AA) for various time points (0.5-24 hr). Incorporation of the fatty acids was maximal by 12 hr. and approximately 85-90% exogenous radiolabeled fatty acid was incorporated into cells by 24 hr. Incorporation of (superscript 14)C-CLA into keratinocytes was slightly lower compared to uptake of
(superscript 14)C-LA or (superscript 14)C-AA. The incorporation (superscript 14)C-LA and (superscript 14)C-CLA into phospholipid fractions was similar: The majority (-57-.) of (superscript 14)C-LA or (superscript 14)C-CLA was incorporated into phosphatidylcholine (PC) with phosphatidylethanolanie (PE) and phosphatidylserine/phosphatidylinositol (PS/PI) containing 15%-27%. In contrast, (superscript 14)C-AA incorporation was evenly distributed into PC (29%), PE(29%) and PS/PI (39%).
Impacts
(N/A)
Publications
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Progress 10/01/94 to 09/30/95
Outputs
No narrative reported at this time.
Impacts
(N/A)
Publications
- NO PUBLICATIONS REPORTED THIS PERIOD.
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