Exercise Enhances Whole-Body Cholesterol Turnover in Mice

PURPOSE: Regular exercise reduces cardiovascular risk in humans by reducing cholesterol levels, but the underlying mechanisms have not been fully explored. Exercise might provoke changes in cholesterol and bile acid metabolism and thereby reduce cardiovascular risk. We examined whether voluntary wheel running in mice modulates cholesterol and bile acid metabolism. METHODS: Male mice (10 wk old) were randomly assigned to have access to a voluntary running wheel for 2 wk (RUN group) or remained sedentary (SED group). Running wheel activity was recorded daily. In a first experiment, fecal sterol outputs, fecal bile acid profiles, plasma parameters, and expression levels of genes involved in cholesterol and bile acid metabolism were determined. In a second experiment, bile flow, biliary bile acid profile, and biliary secretion rates of cholesterol, phospholipids, and bile acids were determined. RESULTS: The RUN group ran an average of 10 km.d and displayed lower plasma cholesterol compared with SED (P = 0.030). Fecal bile acid loss was induced by approximately 30% in running mice compared with SED (P = 0.0012). A approximately 30% increase in fecal cholesterol output in RUN (P = 0.014) was consistent with changes in parameters of cholesterol absorption, such as reduced plasma plant sterol-cholesterol ratio (P = 0.044) and decreased jejunal expression of Npc1l1 (P = 0.013). Supportive of an increased cholesterol synthesis to compensate for fecal sterol loss were increased hepatic mRNA levels of HMGCoA reductase (P = 0.006) and an increased plasma lathosterol-cholesterol ratio (P = 0.0011) in RUN. CONCLUSIONS: Voluntary wheel running increased cholesterol turnover in healthy mice owing to an increased fecal bile acid excretion and a decreased intestinal cholesterol absorption. Enhanced cholesterol turnover may contribute to the established reduction of cardiovascular risk induced by regular exercise.