Activation of PPAR   in colon tumor cell lines by oxidized metabolites of linoleic acid, endogenous ligands for PPAR  

Abstract

The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) gamma plays an important role in the differentiation of intestinal cells and other tissues. Real-time PCR examination of PPAR mRNA for gamma1, gamma2 and gamma3, in Caco-2 and HCT-116 colon cell lines showed that gamma3 is the most abundant message in both lines. Treatment of Caco-2 cells with sodium butyrate, which induces cell differentiation, also leads to an increase in all three PPAR mRNAs. In contrast, treatment of HCT-116 cells with sodium butyrate, which does not lead to differentiation of these cells, causes a decrease in the amount of all three PPAR mRNAs. Furthermore, the amount of PPAR mRNA is greater in Caco-2 cells than in HCT-116 cells at all times examined. As several oxidative metabolites of linoleic acid, including 13-hydroxyoctadecadienoic acid (13-HODE) and 13-oxooctadecadienoic acid (13-OXO) have been shown to bind PPAR, and there is a strong positive correlation between enzymes for metabolism of linoleate oxidation products, intestinal cell differentiation and the distribution of PPAR, we also performed a detailed investigation of the activation of PPAR gamma by 13-HODE and 13-OXO. For these experiments, Caco-2 and HCT-116 cells were transfected with constructs containing PPAR gamma1 or gamma2 then a PPRE-luc reporter construct. Exposure of transfected cells to micromolar concentrations of 13-HODE or 13-OXO produced concentration-dependent increases in luciferase activity. In addition, the two linoleate metabolites activate endogenous PPAR in these cell lines transfected with only PPRE-luc. The data substantiate the contention that oxidation products of linoleic acid are metabolically produced endogenous ligands for PPAR gamma and that PPAR gamma plays an important role in the differentiation of intestinal cells.

Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity

“…These findings concur with prior results obtained from activating PPAR-g via exogenous 13-S-HODE in various cell lines, including colon cancer cell lines (Nagy et al, 1998;Bull et al, 2003), and obtained from expressing 15-LOX-1 in mouse cell lines (Huang et al, 1999). However, our results that endogenous formation of 13-S-HODE in colon cancer cells activates PPAR-g counters previously reported findings in colon cancer cell lines (Nixon et al, 2003).…”

“…13-S-HODE also activates PPAR-g when it is exogenously added in micromolar concentrations (10-30 mM) to the culture medium of cells, including colon cancer cells (Nagy et al, 1998;Bull et al, 2003;Nixon et al, 2003). Thus, the question arises whether 13-S-HODE binding to PPAR-b/d might influence 13-S-HODE activation of PPAR-g.…”

Dietary Intake of ω-6 and ω-3 Fatty Acids and Risk of Colorectal Cancer in a Prospective Cohort of U.S. Men and Women

“…A nested case-control study from the male PHS cohort (35) and a prospective study among Japanese men (33) also observed nonsignificant inverse trends for blood levels of N-6 fatty acids with colorectal cancer risk, whereas prospective cohorts using intake from dietary questionnaires generally found no association in men (23,39,40). Although eicosanoids derived from N-6 fatty acids are generally proinflammatory, some derivatives of LA have been shown to have anticarcinogenic effects (57,58).…”

Stearoyl-CoA Desaturase 2 Is Required for Peroxisome Proliferator-activated Receptor γ Expression and Adipogenesis in Cultured 3T3-L1 Cells

“…Because PPAR␥ appears to be activated by an endogenous ligand during adipogenesis (8,(11)(12)(13)16), we reasoned that if a depleted enzyme is required specifically for the production of a PPAR␥ ligand, the addition of an exogenous ligand may reverse the effect of such enzyme depletion. Thus, in our screen the enzymes were also depleted in the presence of the PPAR␥ specific ligand, rosiglitazone, as a control.…”

“…Because PPAR␥ has a large hydrophobic ligand binding domain (9) and activation occurs in response to fatty acids (10), endogenous long chain fatty acids or their derivatives have been proposed as natural ligands. These include oleate, linoleate, nitrolinoleate, nitrooleate, 9-hydroxydecaenoic acid, arachidonic acid, and 15-deoxy-prostaglandin J2 (11)(12)(13)(14)(15). Despite the many proposed ligands, nitrolinoleate and nitro-oleate are the only fatty acids with a high binding affinity, but it has not yet been verified that these fatty acids are truly endogenous PPAR␥ ligands in adipocytes (13,15).…”