Voluntary exercise increases cholesterol efflux but not macrophage reverse cholesterol transport in vivo in mice

Physical exercise beneficially impacts on the plasma lipoprotein profile as well as on the incidence of cardiovascular events and is therefore recommended in primary and secondary prevention strategies against atherosclerotic cardiovascular disease. However, the underlying mechanisms of the protective effect of exercise remain largely unknown. Therefore, the present study tested the hypothesis that voluntary exercise in mice impacts on cholesterol efflux and in vivo reverse cholesterol transport (RCT). After two weeks of voluntary wheel running (average 10.1 +/- 1.4 km/day) plasma triglycerides were lower (p <0.05), while otherwise lipid and lipoprotein levels did not change. Macrophage cholesterol efflux towards plasma was significantly increased in running (n = 8) compared to sedentary (n = 6) mice (14.93 +/- 1.40 vs. 12.33 +/- 2.60%, p <0.05). In addition, fecal excretion of bile acids (3.86 +/- 0.50 vs. 2.90 +/- 0.51 nmol/d, p = 0.001) and neutral sterols (2.75 +/- 0.43 vs. 1.94 +/- 0.22 nmol/d, p <0.01) was significantly higher in running mice. However, RCT from macrophages to feces remained essentially unchanged in running mice compared with sedentary controls (bile acids: 3.2 +/- 1.0 vs. 2.9 +/- 1.1% of injected dose, n.s.; neutral sterols: 1.4 +/- 0.7 vs. 1.1 +/- 0.5% injected dose, n.s.). Judged by the plasma lathosterol to cholesterol ratio, endogenous cholesterol synthesis was increased in exercising mice (0.15 +/- 0.03 vs. 0.11 +/- 0.02, p <0.05), while the hepatic mRNA expression of key transporters for biliary cholesterol (Abcg5/g8, Sr-bl) as well as bile acid (Abcb11) and phospholipd (Abcb4) excretion did not change. These data indicate that the beneficial effects of exercise on cardiovascular health include increased cholesterol efflux, but do not extend to other components of RCT. The increased fecal cholesterol excretion observed in running mice is likely explained by higher endogenous cholesterol synthesis, however, it does not reflect increased RCT in the face of unchanged expression of key transporters for biliary sterol secretion.