Fatty acid chain length and saturation influences PPARα transcriptional activation and repression in HepG2 cells

Fatty acids regulate peroxisome proliferator activated receptor α (PPARα) activity, however, most studies evaluated the binding ability of fatty acids to PPARα, which does not necessarily result in PPARα transactivation. We therefore examined dose-response relationships between fatty acids and PPARα transactivation in HepG2 cells. Secretion of apoA-I protein as well as CPT1, ACO, and PPARα mRNA expression, all accepted PPARα targets, were determined as read-outs.

HepG2 cells transfected with full-length human PPARα and a PPAR response element luciferase reporter were exposed to different fatty acid concentrations. Lauric and lower doses of myristic acid increased PPARα transactivation. Palmitic and stearic acid inhibited and their monounsaturated counterparts, palmitoleic and oleic acid, increased PPARα transactivation. Linoleic and γ-linolenic acid did not influence PPARα transactivation, while α-linolenic acid strongly increased transactivation. Arachidonic, eicosapentaenoic acid, and docosahexaenoic acid all activated PPARα transactivation at lower doses, but acted at higher concentrations as PPARα repressors. In line with these results, α-linolenic acid increased and docosahexaenoic acid decreased apoA-I protein secretion and PPARα mRNA expression. Interestingly, ACO mRNA expression did not change while CPT1 mRNA expression showed the opposite pattern.

We found that fatty acids, reported to bind strongly to PPARα, could even repress PPARα transactivation illustrating that these binding assays should be interpreted with caution.