Mechanisms of action and biomarkers

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Abstract Examples


Belury MA, Kavanaugh CJ, Liu KL. Conjugated linoleic acid modulates phorbol ester-induced PPARdelta and K-FABP mRNA expression in mouse skin. Nutr Res 2007.

Conjugated linoleic acid (CLA) inhibits mouse skin carcinogenesis. Treatment of mouse skin with the phorbol ester tetradecanoylphorbol-13-acetate (TPA) significantly increased peroxisome proliferator-activated receptor delta (PPAR-delta) mRNA expression 6 hours after treatment. When mice were fed a diet with 0.5% to 1.5% CLA, TPA-induced PPAR-delta mRNA expression decreased (P < .05). In contrast, 1.5% dietary CLA significantly increased TPA-modulated PPAR-delta mRNA expression compared with acetone-treated control (P < .05) when measured 18 hours after exposure. Keratinocyte fatty acid binding protein (K-FABP) mRNA was elevated in TPA-treated mouse epidermis compared with acetone treatment, and dietary CLA significantly decreased TPA-induced K-FABP mRNA expression (P <.05). Moreover, mRNA accumulation of PPAR-delta and K-FABP was higher in mouse skin papillomas than in normal mouse epidermis, regardless of whether mice were fed CLA or when skin was exposed to different PPAR ligand treatments during the promotion stage of mouse skin tumorigenesis. Because PPAR-delta and K-FABP are involved in skin tumor promotion, the fact that CLA regulates TPA-modulated PPAR- and K-FABP mRNA expression may begin to explain the mechanisms of CLA for inhibiting skin cancer.


Liu LF, Purushotham A, Wendel AA, Belury MA. Combined effects of rosiglitazone and conjugated linoleic acid on adiposity, insulin sensitivity and hepatic steatosis in high fat fed mice. Am J Physiol Gastrointest Liver Physiol 2007.

Dysfunctional cross-talk between adipose tissue and liver tissue results in metabolic and inflammatory disorders. As an insulin sensitizer, rosiglitazone (ROSI) improves insulin resistance yet causes increased adipose mass and weight gain in mice and humans. Conjugated linoleic acid (CLA) reduces adipose mass and body weight gain but induces hepatic steatosis in mice. We examined the combined effects of ROSI and CLA on adiposity, insulin sensitivity and hepatic steatosis in male C57Bl/6 mice fed a high fat diet. CLA suppressed weight gain and adipose mass but caused hepatic steatosis. Addition of ROSI attenuated CLA-induced insulin resistance and dysregulation of adipocytokines. In adipose, CLA significantly suppressed lipoprotein lipase, fatty acid translocase FAT/CD36 mRNA and addition of ROSI completely rescued this effect. CLA increased markers of macrophage infiltration F4/80 and CD68 mRNA levels without inducing tumor necrosis factor alpha (TNFalpha) in epididymal adipose tissue. The ratio of Bax/Bcl2 was significantly increased in adipose of CLA group, and was partially prevented by co-treatment with ROSI. In the liver, CLA increased microsteatosis and surprisingly increased the rate of very low density lipoprotein-TG production without inducing TNFalpha and markers of macrophage infiltration. These changes were accompanied by significantly increased mRNA levels of stearoyl-CoA desaturase, FAT/CD36 and fatty acid synthase. The combined administration of CLA and ROSI (CLA/ROSI) reduced hepatic liver triglyceride content as well as lipogenic gene expression when compared to CLA alone.


Lala G, Malik M, Zhao C, He J, Kwon Y, Giusti MM, Magnuson BA. Anthocyanin-rich extracts inhibit multiple biomarkers of colon cancer in rats. Nutr. Cancer 2006.

The aim of the present study was to investigate the chemoprotective activity of anthocyanin-rich extracts (AREs) from bilberry (Vaccinium myrtillus L.), chokeberry (Aronia meloncarpa E.), and grape (Vitis vinifera) by assessing multiple biomarkers of colon cancer in male rats treated with a colon carcinogen, azoxymethane. Fischer 344 male rats were fed the AIN-93 diet (control) or AIN-93 diet supplemented with AREs for 14 wk. Biomarkers that were evaluated included the number and multiplicity of colonic aberrant crypt foci (ACF), colonic cell proliferation, urinary levels of oxidative DNA damage, and expression of cyclooxygenase (COX) genes. To assess the bioavailability, levels of anthocyanins in serum, urine, and feces were evaluated. Total ACF were reduced (P<0.05) in bilberry, chokeberry, and grape diet groups compared with the control group. The number of large ACF was also reduced (P<0.05) in bilberry and chokeberry ARE-fed rats. Colonic cellular proliferation was decreased in rats fed bilberry ARE and chokeberry ARE diets. Rats fed bilberry and grape ARE diets had lower COX-2 mRNA expression of gene. High levels of fecal anthocyanins and increased fecal mass and fecal moisture occurred in ARE-fed rats. There was also a significant reduction (P<0.05) in fecal bile acids in ARE-fed rats. The levels of urinary 8-hydroxyguanosine were similar among rats fed different diets. These results support our previous in vitro studies suggesting a protective role of AREs in colon carcinogenesis and indicate multiple mechanisms of action.