Cla Modulation Of Lipid Metabolism And Gene Expression

The No Nonsense Teds Fat Melting

Eat More Diet Less

Get Instant Access

As previously discussed, diets with CLA result in an accumulation of CLA, especially the 9,11-CLA isomer in phospholipids of tissues, and modify subsequent eicosanoid production (Figure 24.2).1 The role of CLA in reducing cycloox-ygenase products (e.g., PGE2, PGF2a) has been shown in bone and macrophages,8081 the epidermis of mice,64 rat colons,65 and keratinocytes,82 but not small intestine tissue of Min mice,48 spleen of rats,81 and MCF-7 cells.26 CLA also reduced accumulation of the lipoxygenase products leukotriene-B4 and -C4 in spleen and lung81 but not 14C-hydroxyeicosatetraenoic acid (14C-12-HETE) in cultured human platelets.83 It suggests that CLA modulation of eicosanoid production may be tissue specific, and its inhibition of carcinogenesis in some tissues may involve the reduction of arachidonate-derived eicosanoids by one of three mechanisms.

First, CLA may displace arachidonate incorporation into phospholipids as shown in cultured keratocytes82 and colonic mucosa of rats.65 Dietary CLA displaces the arachidonate precursor, linoleate, in a dose-responsive manner in livers of mice fed various doses of CLA (0.5 to 1.5 g/100 g) in one study51 but not others.52,82

A second explanation for the reduction of arachidonate-derived eicosanoids by CLA may be through inhibition of the constitutive enzymes, cyclooxygenases (COX)-1, and/or the inducible form, COX-2, at the level of mRNA, protein, or activity.8485 CLA or elongated and desaturated products from CLA (e.g., conjugates

Membrane phospholipids

Dietary or endogenous sources of arachidonate

Phospholipase

Arachidonate (20:4) or conjugated-arachidonate (20:4)

Cyclooxygenase

Arachidonate (20:4) or conjugated-arachidonate (20:4)

Cyclooxygenase

Lipoxygenase

Inflammation, vascularization and tumor promotion

Prostaglandins Thromboxanes

Inflammation, vascularization and tumor promotion

A6 Desaturase/ Elongase/

A5 Desaturase

Lipoxygenase

Dietary or endogenous sources for linoleate or CLA

Hydroxyeicosatetraenoate

Leukotrienes

Events in immune response and inflammation

FIGURE 24.2 General schematic pathway for eicosanoid synthesis from arachidonic acid. (From Belury MA. Annu Rev Nutr 2002; 22:505-531. With permission.)

of either arachidonate or eicosatetraenoate) may act as antagonists for COX thereby reducing available enzymes (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-184 and COX-2 at the levels of mRNA and protein in a cultured macrophage cell line.85

CLA may modulate lipid metabolism in part by a third mechanism dependent on the activation of the nuclear hormone receptors, peroxisome proliferator-activated receptors (PPARs).1 It has been shown that CLA moderates affinity for binding to and activating PPARy,8687 and modulates transcription of genes responsive to PPARy in adipose tissue in vivo15 and in vitro.85 PPARy is found in extrahepatic tissues such as adipose, prostate, colon, and mammary gland, and is a required factor in adipose tissue differentiation.88 In addition to evidence showing that CLA may induce PPARy-responsive genes in vivo, CLA may increase the level of PPARy itself.89 Because activators of PPARy are protective against cancers arising in the mammary gland, colon, and prostate,18 90 it is possible that some of the molecular mechanisms of action of CLA on carcino-genesis are mediated by PPARy. The ability of PPARy to mediate effects of CLA is through increased levels of PPARy protein89 or through activation of PPARy by downstream metabolites of CLA, such as desaturase and elongase products.86 By blocking A6 desaturase using synthetic inhibitor SC-26196,91 the ability of CLA isomers to activate PPARy was significantly reduced.1 These data suggest that activation of PPARy by CLA is increased by the formation of the A6 desat-urated products from CLA, c6,c9,t11-CLA, or c6,t10,c12-CLA, but the activation of PPARy by these products is yet to be determined.

24.5 CLA INTAKE AND CANCER IN HUMANS

There is limited evidence for a direct association between CLA intake and cancer in humans. An inverse relationship has been found between milk consumption and breast cancer risk in women, suggesting that some of this protective effect may be due to CLA in milk.92 Typical CLA intake has been estimated to be 52 mg/day among young men,93 137 mg/day among women,94 and 227 mg/day among lactating women14 in the U.S., and 430 and 350 mg/day for German men and women.95 It has been shown that CLA level in breast adipose tissue was lower in patients who had localized breast cancer (n = 261, cases) than in those treated for a benign breast tumor (n = 99, controls; 96). The majority of CLA was in sn-1 and sn-3 position within the triacylglycerol molecule in both the case and control population, but the difference was greater in the control than in the case.96 Because the isomers of CLA in breast adipose tissue were similar to those found in many food items, differences in the dietary intake of CLA at least partially explain the differences in breast adipose tissue CLA content between the cases and controls.96 However, in the Netherlands Cohort Study, estimated CLA intake was reported to demonstrate a positive (albeit weak) relation with breast cancer incidence in postmenopausal women.97 Thus, there is insufficient evidence from epidemiologic studies in humans; future studies are warranted on the relationship between blood levels of CLA isomers and their metabolites and breast cancer risk.

24.6 CONCLUSION

CLA inhibits carcinogenesis in numerous animal models and cell cultures at multiple stages, offering the possibility that several types of cancer in humans may be prevented with a diet rich in CLA. Extrapolation of dietary CLA concentrations that are effective in animal models indicates that equivalent CLA concentrations in a 70-kg human would be on the order of 3.5 g/day, which is significantly higher than the estimated consumption in the U.S.

Before any dietary recommendation can be made, limitations of the available evidence must be recognized. First, there is insufficient evidence based on human epidemiological data and it is difficult to evaluate from such data the impact of CLA alone because of its high correlation with fat intake. While case-control studies implicate a high-fat diet as a risk factor for breast cancer, cohort studies often show a negative association. Second, although c9,t11-isomer is postulated as the most biological form of CLA, it is difficult to predict which isomer of CLA is the putative candidate. Third, the kinetics of CLA incorporation in the phospholipids and the mechanisms whereby CLA exerts its effects are not well understood. These three limitations warrant further work to understand the implications of dietary CLA and the possibility of lowering the risk from human cancer development.

Was this article helpful?

0 0
Weight Loss Funnel

Weight Loss Funnel

Who Else Wants To Discover The 3 Most Effective Fat Burning Methods The Weight Loss Industry Does NOT Want You To Know About.

Get My Free Ebook


Post a comment