Hepatic Scavenger Receptor Class B Type 1 Knockdown Reduces Atherosclerosis and Enhances the Antiatherosclerotic Effect of Brown Fat Activation in APOE*3-Leiden.CETP Mice

Objective: Brown fat activation attenuates atherosclerosis development by accelerating triglyceride-rich lipoprotein turnover and/or stimulation of reverse cholesterol transport via the SRB1 (scavenger receptor class B type 1). The aim this study was to investigate specific role hepatic in atheroprotective properties brown activation. Approach and Results: APOE*3-Leiden.CETP mice, a well-established model human-like metabolism atherosclerosis, were treated with vehicle or adenoassociated virus serotype 8-short hairpin RNA, which decreased protein levels 40% 55%. After 2 weeks, mice without knockdown β3-adrenergic agonist CL316 243 activate for 4 weeks determine HDL (high-density lipoprotein) catabolism 9 evaluate atherosclerosis. Surprisingly, additively improved beneficial effects agonism on development. In fact, per se not only increased HDL-cholesterol but also reduced plasma triglyceride non-HDL-cholesterol levels, thus explaining reduction Mechanistic studies indicated that is due lipolytic processing uptake VLDL (very low density facilitating VLDL-surface transfer HDL. Conclusions: Hepatic mouse an intact ApoE (apolipoprotein E)-LDLR (low receptor) clearance pathway, relevant human metabolism, effect development, explained pleiotropic VLDL. could be effective strategy treat cardiovascular disease subjects impaired function.