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

Atherogenic dyslipidemia and chronic inflammation appear strongly associated with residual cardiovascular disease (CVD) risk. Peroxisome proliferator-activated receptor a (PPARa) 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. Thus, we performed single-nucleus RNA sequencing (snRNA-seq) to better understand the hepatic-specific molecular actions of PPARa and their distal effects on atherosclerotic plaque development. Hepatic PPARa activation limits a pro-inflammatory phenotype in hepatocytes and reduces leukocyte recruitment. This study highlights a non-lipid, anti-inflammatory mechanism of hepatic PPARa with implications for cardiovascular disease modulation. Overall design: Nuclei were isolated from frozen liver tissues of three biologically independent mice per group after 8 weeks of western diet supplemented or not with pemafibrate, and purified by Fluorescence-activated cell sorting (FACS). Nuclei integrity was visually verified with Trypan blue staining and counted before snRNA-seq analysis.