PPARa has long been known as a key regulator of mammalian fatty acid oxidation during fasting. However, high PPARa expression is restricted to a limited number of tissues, mainly liver, kidney, brown adipose tissue and the myocardium. Recently also the ubiquitously expressed PPARd was reported to stimulate fatty acid oxidation when activated by agonists in myocytes, cardiomycytes and adipo-cytes. A role for PPARd as regulator of basal fatty acid catabolism and energy expenditure was therefore suggested. Here we show that PPARd is the most abundantly expressed PPAR subtype in both primary pancreatic islets and in the insulinoma cell line INS-1E. This is reflected at the functional level in activity assays using a PPRE-driven luciferase reporter construct. The fatty acids oleic, arachidonic and linolenic acid are able to acivate this construct synergistically with the synthetic RXR agonist LG100268. Selective activation of PPARd in INS-1E cells with the PPARd agonist L165041 in the presence or absence of the RXRa agonist LG100268 induces luciferase activity 3- and 7-fold respectively and mimics the effect of the fatty acids. The same subset genes involved in fatty acid uptake and oxidation are synergistically activated by fatty acids and the selective PPARd and RXRa agonists. This effect is blunted by specific knockdown of PPARd. In addition, we show that ectopically expressed PPARd and RXRa are able synergistically to recruit RNA polymerase II, TBP and TRAP220 to the promoters of known PPAR target genes in vivo. In parallel with increased expression of genes involved in fatty oxidation, b-oxidation of 14C-oleate is increased 7-fold upon incubation of INS-1E cells with L165041 and LG100268. In keeping with this, adenoviral co-expression of PPARd and RXRa leads to a 5-fold increase in 14C-oleate oxidation. The current observations suggest that PPARd is an important lipid sensor and regulator of lipid oxidation in pancreatic b-cells.
Main Research Area:
Keystone Synposia - Bioactive Lipids, Lipidomics and their Targets, 2005