title: Bile acid sequestration normalizes plasma cholesterol and reduces atherosclerosis in hypercholesterolemic mice. No additional effect of physical activity.
abstract: OBJECTIVE
  Bile acid sequestrants (BAS) and physical activity (RUN) decrease incidence of cardiovascular events. Both treatments are often prescribed, yet it is not known whether their beneficial effects are additive. We assessed the effects of BAS treatment alone and in combination with RUN on cholesterol metabolism, heart function and atherosclerotic lesion size in hypercholesterolemic mice.
  
  
  METHODS
  Male Ldlr-deficient mice remained either sedentary (CONTROL), were treated with Colesevelam HCl (BAS), had access to a running wheel (RUN), or were exposed to BAS and RUN (BAS RUN). All groups were fed a high cholesterol diet for 12 weeks. Then, feces, bile and plasma were collected. Atherosclerotic lesion size was determined in the aortic arch and heart function by echocardiography.
  
  
  RESULTS
  BAS RUN ran more than RUN (6.4 ± 1.4 vs. 3.5 ± 1.0 km/day, p < 0.05). BAS and BAS RUN displayed ~3-fold reductions in plasma cholesterol levels (p < 0.001), ~2.5-fold increases in fecal neutral sterol (p < 0.001) and bile acid (p = 0.01) outputs, decreases in biliary secretions of cholesterol (~6-fold, p < 0.0001) and bile acids (~2-fold, p < 0.001) vs. CONTROL while no significant effects were observed in RUN. Compared to CONTROL, lesion size decreased by 78% in both BAS and BAS RUN, (p < 0.0001).
  
  
  CONCLUSIONS
  BAS reduce atherosclerosis in Ldlr-deficient mice, coinciding with a switch from body cholesterol accumulation to cholesterol loss. RUN slightly modulated atherosclerotic lesion formation but the combination of BAS and RUN had no clear additive effects in this respect.
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Maxi
authors.initials: M
authors.lastname: Meissner
authors.forename: Henk
authors.initials: H
authors.lastname: Wolters
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.forename: Renze
authors.initials: R
authors.lastname: Boverhof
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Bloks
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
mesh_terms: D000499:Allylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000821:Animal Feed; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001011:Aorta / Q000000981:diagnostic imaging / Q000378:metabolism; D050197:Atherosclerosis / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology*; D001647:Bile Acids and Salts / Q000378:metabolism*; D002302:Cardiac Output / Q000502:physiology; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood; D000069472:Colesevelam Hydrochloride; D004452:Echocardiography; D005243:Feces; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D013261:Sterols / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D011973:Receptors, LDL; D013261:Sterols; D000499:Allylamine; D002784:Cholesterol; D000069472:Colesevelam Hydrochloride