Peroxisome proliferator-activated receptor alpha is not the exclusive mediator of the effects of dietary cyclic FA in mice.

Cyclic FA monomers (CFAM) formed during heating of alpha-linolenic acid have been reported to interfere in hepatic metabolism in a putatively peroxisome proliferator-activated receptor alpha (PPARalpha)-dependent manner. In the present work, CFAM (0.5% of the diet) were administered for 3 wk to wild-type and PPARalpha-null mice of both genders to elucidate the role of PPARalpha in mediating the effects of CFAM on the activity of acyl-CoA oxidase (ACO) and omega-laurate hydroxylase (CYP4A), the regulation of which is known to be dependent on the PPARalpha. Dietary CFAM enhanced CYP4A activity threefold in male and female wild-type mice. This effect was abolished in PPARalpha-null mice. A twofold induction of ACO activity was found in wild-type female mice fed CFAM; however, no effect was seen in males. In wild-type animals, (omega-1)-laurate hydroxylase (CYP2E1) activity, the expression of which has not been shown to be PPARalpha dependent, was not affected by the CFAM diet. In contrast, stearoyl-CoA desaturase activity was reduced in wild-type mice. CFAM feeding reduced the activities of ACO, CYP2E1, and stearoyl-CoA desaturase and caused accumulation of lipids in the livers of female PPARalpha-null mice. These data show that CFAM apparently activate gene expression via the PPARalpha and have profound effects on lipid homeostasis, exacerbating the disturbances preexisting in mice lacking functional PPARalpha. Although the data emphasize the importance of PPARalpha in the metabolism of the CFAM, these results show that PPARalpha is not the exclusive mediator of the effects of CFAM in lipid metabolism in mice.