Title: Treadmill Exercise Training Modulates Hepatic Cholesterol Metabolism and Circulating PCSK9 Concentration in High Fat Fed Mice
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a novel biomarker of LDL clearance and therapeutic target of cardiovascular disease risk. We examined the effects of aerobic exercise training in modulating PCSK9 abundance and hepatic sterol regulation in high fat fed C57BL/6 mice. Mice (n=8/group) were assigned to a low fat (LF), high fat (HF), or a HF with exercise (HF+EX) group for 8 weeks. The HF+EX group was progressively trained 5 days/week on a motorized treadmill. The HF+EX group was protected against body weight (BW) gain and diet-induced dyslipidemia compared with the HF group. The HF+EX group demonstrated an increase in hepatic PCSK9 mRNA (1.9 fold of HF control, p<0.05) and a reduction in plasma PCSK9 (14%) compared with the HF group. Compared with HF mice, HF+EX mice demonstrated reduced hepatic cholesterol (14%) and increased (p<0.05) nuclear SREBP2 protein (1.8 fold of HF group) and LDLr mRNA (1.4 fold of HF group). Plasma PCSK9 concentrations correlated positively with plasma non-HDL-C (p=0.01, r = 0.84). Results suggest that treadmill exercise reduces non-HDL cholesterol and differentially modulates hepatic and blood PCSK9 abundance in HF-fed C57BL/6 mice.