Abstract
Conjugated linoleic acid (CLA) has the unique property of inducing regression of pre-established murine atherosclerosis. Understanding the mechanism(s) involved may help identify endogenous pathways that reverse human atherosclerosis. Here, we provide evidence that CLA inhibits foam cell formation via regulation of the nuclear receptor coactivator, peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α, and that macrophage PGC-1α plays a role in atheroprotection in vivo. PGC-1α was identified as a hub gene within a cluster in the aorta of the apoE−/− mouse in the CLA-induced regression model. PGC-1α was localized to macrophage/foam cells in the murine aorta where its expression was increased during CLA-induced regression. PGC-1α expression was also detected in macrophages in human atherosclerosis and was inversely linked to disease progression in patients with the disease. Deletion of PGC-1α in bone marrow derived macrophages promoted, whilst over expression of the gene inhibited foam cell formation. Importantly, macrophage specific deletion of PGC-1α accelerated atherosclerosis in the LDLR−/− mouse in vivo. These novel data support a functional role for PGC-1α in atheroprotection.
Highlights
Conjugated linoleic acid (CLA) is a generic term denoting a group of naturally occurring isomers of linoleic acid (18:2, n6), which vary in the position and geometry of their double bonds (Mitchell & McLeod, 2008)
PGC‐1a expression is increased in CLA‐induced regression of atherosclerosis in the apoEÀ/À model We have previously shown that 4 week supplementation of CLA blend induces regression of atherosclerosis in the apoEÀ/À mouse (Toomey et al, 2006)
A critical step in the development of atherosclerosis is the accumulation of cholesterol in macrophages, which leads to foam cell formation
Summary
Conjugated linoleic acid (CLA) is a generic term denoting a group of naturally occurring isomers of linoleic acid (18:2, n6), which vary in the position and geometry of their double bonds (Mitchell & McLeod, 2008). We have previously shown that dietary administration of a 1% CLA blend (80:20, cis9,trans11‐CLA:trans10,cis12‐CLA) induces regression of pre‐ established atherosclerosis in the apoEÀ/À mouse model despite continuing a high cholesterol challenge (Toomey et al, 2006). We reported that macrophage cell accumulation was reduced in the atherosclerotic plaques of CLA‐fed mice suggesting this cell as a potential target for CLA (Toomey et al, 2006).
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