title: Voluntary wheel running increases bile acid as well as cholesterol excretion and decreases atherosclerosis in hypercholesterolemic mice.
abstract: OBJECTIVE
  Regular physical activity decreases the risk for atherosclerosis but underlying mechanisms are not fully understood. We questioned whether voluntary wheel running provokes specific modulations in cholesterol turnover that translate into a decreased atherosclerotic burden in hypercholesterolemic mice.
  
  
  METHODS
  Male LDLR-deficient mice (8 weeks old) had either access to a voluntary running wheel for 12 weeks (RUN) or remained sedentary (CONTROL). Both groups were fed a western-type/high cholesterol diet. Running activity and food intake were recorded. At 12 weeks of intervention, feces, bile and plasma were collected to determine fecal, biliary and plasma parameters of cholesterol metabolism and plasma cytokines. Atherosclerotic lesion size was determined in the aortic root.
  
  
  RESULTS
  RUN weighed less (∼13%) while food consumption was increased by 17% (p=0.004). Plasma cholesterol levels were decreased by 12% (p=0.035) and plasma levels of pro-atherogenic lipoproteins decreased in RUN compared to control. Running modulated cholesterol catabolism by enhancing cholesterol turnover: RUN displayed an increased biliary bile acid secretion (68%, p=0.007) and increased fecal bile acid (93%, p=0.009) and neutral sterol (33%, p=0.002) outputs compared to control indicating that reverse cholesterol transport was increased in RUN. Importantly, aortic lesion size was decreased by ∼33% in RUN (p=0.033).
  
  
  CONCLUSIONS
  Voluntary wheel running reduces atherosclerotic burden in hypercholesterolemic mice. An increased cholesterol turnover, specifically its conversion into bile acids, may underlie the beneficial effect of voluntary exercise in mice.
authors.affiliation: Department of Pediatrics, University of Groningen, Groningen, The Netherlands. meissner.maxi@gmail.com
authors.forename: Maxi
authors.initials: M
authors.lastname: Meissner
authors.forename: Elisa
authors.initials: E
authors.lastname: Lombardo
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D001835:Body Weight; D002784:Cholesterol / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism*; D008297:Male; D051379:Mice; D009043:Motor Activity; D010805:Physical Conditioning, Animal; D011973:Receptors, LDL / Q000235:genetics; D012306:Risk; D012420:Running
chemical_list: D001647:Bile Acids and Salts; D016207:Cytokines; D011973:Receptors, LDL; D002784:Cholesterol