Dietary oxidized linoleic acid lowers triglycerides via APOA5/APOClll dependent mechanisms

Abstract

Previously we have shown that intestinal cells efficiently take up oxidized fatty acids (OxFAs) and that atherosclerosis is increased when animals are fed a high cholesterol diet in the presence of oxidized linoleic acid. Interestingly, we found that in the absence of dietary cholesterol, the oxidized fatty acid fed low-density lipoprotein (LDL) receptor negative mice appeared to have lower plasma triglyceride (TG) levels as compared to animals fed oleic acid. In the present study, we fed C57BL6 mice a normal mice diet supplemented with oleic acid or oxidized linoleic acid (at 18 mg/animal/day) for 2 weeks. After the mice were sacrificed, we measured the plasma lipids and collected livers for the isolation of RNA. The results showed that while there were no significant changes in the levels of total cholesterol and high-density lipoprotein cholesterol (HDLc), there was a significant decrease (41.14%) in the levels of plasma TG in the mice that were fed oxidized fatty acids. The decreases in plasma TG levels were accompanied by significant increases (P<0.001) in the expressions of APOA5 and acetyl-CoA oxidase genes as well as a significant (P<0.04) decrease in APOClll gene expression. Oxidized lipids have been suggested to be ligands for peroxisome proliferator-activated receptor (PPAR*). However, there were no increases in the mRNA or protein levels of PPAR* in the oxidized linoleic acid fed animals. These results suggest that oxidized fatty acids may act through an APOA5/APOClll mechanism that contributes to lowering of TG levels other than PPAR* induction.

Fig. 1

(A) PPARα gene expression. Mice PPARα gene expression have not shown significant difference between the control and 13-HPODE fed mice. Values are means ± S.D. (B) Western blot analysis of PPARα in the liver is shown. Gels were immunoblotted by using anti-PPARα and anti-β-actin (used as an internal control) antibodies. Control mice on oleic acid mixed chow (n = 9) were compared to experimental mice on 13-HPODE mixed chow (n = 9), results did not show significant difference between the two groups; data is represented by three mice from control group, and four from experimental mice.

Fig. 2

Mice hepatic lipase gene expression. The hepatic lipase gene expression was significantly down regulated among the experimental mice fed 13-HPODE when compared to control (P ≤ 0.007). Values are means ± S.D.

Fig. 3

Mice acetyl-CoA oxidase gene expressions. Acetyl-CoA oxidase gene expression was significantly upregulated among mice supplemented with diet mixed with 13-HPODE (P ≤ 0.02). Values are means ± S.D.

Fig. 4

Mice APOA5 and APOClll gene expression. APOA5 was significantly upregulated (P ≤ 0.001) among mice supplemented with diet containing 13-HPODE; however APOClll was significantly (P 0.04) down regulated in this group compared to the control mice fed diet containing oleic acid. Data expressed as means ± S.D. Open bars represent control group whereas the black bars represent the experimental mice on 13-HPODE supplemented diet.