Anti-inflammatory, but not lipid-lowering, activity of hepatocyte PPARα improves atherosclerosis in Ldlr-deficient...

Atherogenic dyslipidemia and chronic inflammation appear strongly associated with residual cardiovascular disease (CVD) risk. Peroxisome proliferator-activated receptor α (PPARα) agonists, which exert both triglyceride-lowering and anti-inflammatory properties, are potential therapeutic candidates to target residual CVD risk. However, CVD outcome studies with these drugs have yielded mixed results for currently unclear reasons. In this study, we compared the impact of hepatocyte anti-inflammatory (transrepression) versus lipid-lowering (transactivation) properties of PPARα agonism on atherosclerosis in Ldlr^-/- mice. PPARα agonist treatment reduced aortic atherosclerotic plaque surface in Western diet-fed Ldlr^-/- mice expressing in hepatocytes either PPARα^WT or a transrepression-selective PPARα mutant (PPARα^DISS), despite the lack of atherogenic dyslipidemia improvement with PPARα^DISS. Mechanistically, ligand-activated hepatocyte-specific transrepressive PPARα activity decreased the pro-inflammatory phenotype of hepatocytes, lowered the recruitment of leukocytes in the liver, reduced plasma IL-1β concentrations, and decreased atherosclerotic plaque macrophage content. These findings identify a distal effect of hepatic PPARα on vascular integrity rather linked to its anti-inflammatory activity than its lipid-lowering actions and highlight an essential role of targeting inflammation in CVD.