Abstract 43: Activation of the Nuclear Receptor Coactivator PGC-1α Mediates an Atheroprotective Effect

Abstract

Supplementing dietary chow with conjugated linoleic acid (CLA) induces marked regression of pre-established murine atherosclerosis, in contrast to other PPAR agonists. The finding suggests that there are unidentified endogenous pathways that suppress the progression or promote the regression of atherosclerosis. Identifying these pathways in the mouse and their homologues in humans may help elucidate the mechanisms of the disease and targets for future therapies. Here, we provide evidence that CLA inhibits foam cell formation via regulation of the nuclear receptor co-activator, PGC-1α in a manner that differs from PPAR activation. Gene expression analysis was performed in the aorta of ApoE -/- mice following induction of atherosclerosis and dietary supplementation with/without CLA. CLA induced dramatic regression of the cholesterol-induced atherosclerosis. PGC-1α was identified as a ‘hub’ gene within a cluster of genes induced by CLA in the aorta of the ApoE -/- during regression. PGC-1α protein was also found in murine and human atherosclerotic plaque, where it was localised to macrophage/foam cells. In a mouse macrophage cell line exposed to oxLDL, CLA induced PGC-1α and several genes in the network in an isomer specific fashion, including RORαand ABCA1. CLA also induced the PGC-1α target genes Cyp7b1 and UCP-1, and PPAR. CLA inhibited foam cell formation in the same cells exposed to oxLDL and suppressed the expression of the scavenger receptors, SRA-1 and CD36. Expression of the PGC-1α in macrophages had similar effects. Thus, over-expression of PGC-1α limited the accumulation of oxLDL and subsequent foam cell formation, while deletion of the gene promoted foam cell formation in bone marrow derived macrophages upon exposure to oxLDL. Moreover, deletion of PGC-1α prevented the inhibition of macrophages/foam cell formation by CLA. The nuclear receptor co-activator PGC-1α is a hub gene in a network of genes activated in the aorta during CLA-induced regression of atherosclerosis and mediates CLA’s inhibition of foam cell formation. PGC-1α is also is also expressed in human plaques where its expression is inversely associated with disease progression, raising the possibility that this pathway if activated could regulate human atherosclerosis.