Treadmill Exercise Training Modulates Hepatic Cholesterol Metabolism and Circulating PCSK9 Concentration in High-Fat-Fed Mice

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a novel biomarker of LDL clearance and a therapeutic target of cardiovascular disease. 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) were assigned to a low-fat (LF), high-fat (HF), or an 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.

Exercise training increased gene expression of LDL-R and PCSK9 in intestine: link to transintestinal cholesterol excretion

“…On the other hand, it was also reported that treadmill exercise resulted in increased LDL-R, PCSK9 and SREBP-2 mRNA expression in liver of high-fat-fed C57BL/6 mice. Reduction in hepatic cholesterol accumulation was mentioned as a main reason for higher hepatic LDL-R, PCSK9 transcript by treadmill exercise in high-fat-fed C57BL/6 mice (Wen et al 2013). It seems that higher hepatic cholesterol content in Chol-fed rats in our study is an underlying reason for lower hepatic LDL-R, PCSK9 transcript and consequently suppression of cholesterol uptake from plasma.…”

LDL Receptor and Pcsk9 Transcripts are Decreased in Liver of Ovariectomized Rats: Effects of Exercise Training

“…In rodents, treadmill exercise has been reported to increase liver ABCA1 mRNA levels in healthy rats [ 22 ] . Treadmill exercise also increased liver LDL-R, Pcsk9 and SREBP-2 mRNA in high-fat-fed C57BL/6 mice [ 23 ] while SR-B1 protein has been reported to be unchanged [ 24 ] . However, whether exercise training aff ects hepatic LDL-R, Pcsk9, Lrp1, and SR-B1 gene expression in Ovx animals is unknown.…”

Chronic Exercise Reduces CETP and Mesterolone Treatment Counteracts Exercise Benefits on Plasma Lipoproteins Profile: Studies in Transgenic Mice

“…High-intensity resistance exercise increased non-HDL cholesterol in hamsters fed a hypercholesterolemic diet [41]. On the other hand, wild-type and LDL receptor knockout mice fed with an atherogenic diet had reduced LDL by exercise training [42,43]. Therefore, this effect seems to be related to the species background and/or to the presence of a high-fat diet.…”

“…However, in animal models, the effects on the LDL fraction are more variable; for instance, Von Duvillard et al [40] observed an increase in the LDLcholesterol fraction in pigs fed a hyperlipidemic diet and exercised. On the other hand, wild-type and LDL receptor knockout mice fed with an atherogenic diet had reduced LDL by exercise training [42,43]. On the other hand, wild-type and LDL receptor knockout mice fed with an atherogenic diet had reduced LDL by exercise training [42,43].…”