title: BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice.
abstract: Bacille-Calmette-Guérin (BCG), prepared from attenuated live Mycobacterium bovis, modulates atherosclerosis development as currently explained by immunomodulatory mechanisms. However, whether BCG is pro- or anti-atherogenic remains inconclusive as the effect of BCG on cholesterol metabolism, the main driver of atherosclerosis development, has remained underexposed in previous studies. Therefore, we aimed to elucidate the effect of BCG on cholesterol metabolism in addition to inflammation and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established model of human-like lipoprotein metabolism.
  
  
  
  Hyperlipidemic APOE*3-Leiden.CETP mice were fed a Western-type diet containing 0.1% cholesterol and were terminated 6 weeks after a single intravenous injection with BCG (0.75 mg; 5 × 10(6) CFU).
  
  
  
  BCG-treated mice exhibited hepatic mycobacterial infection and hepatomegaly. The enlarged liver (+53%, p = 0.001) coincided with severe immune cell infiltration and a higher cholesterol content (+31%, p = 0.03). Moreover, BCG reduced plasma total cholesterol levels (-34%, p = 0.003), which was confined to reduced nonHDL-cholesterol levels (-36%, p = 0.002). This was due to accelerated plasma clearance of cholesterol from intravenously injected [(14)C]cholesteryl oleate-labelled VLDL-like particles (t½ -41%, p = 0.002) as a result of elevated hepatic uptake (+25%, p = 0.05) as well as reduced intestinal cholestanol and plant sterol absorption (up to -37%, p = 0.003). Ultimately, BCG decreased foam cell formation of peritoneal macrophages (-18%, p = 0.02) and delayed atherosclerotic lesion progression in the aortic root of the heart. BCG tended to decrease atherosclerotic lesion area (-59%, p = 0.08) and reduced lesion severity.
  
  
  
  BCG reduces plasma nonHDL-cholesterol levels and delays atherosclerotic lesion formation in hyperlipidemic mice.
authors.affiliation: Dept. of Medicine, Div. of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands. Electronic address: a.d.van_dam@lumc.nl.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: van Dam
authors.affiliation: Dept. of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Siroon
authors.initials: S
authors.lastname: Bekkering
authors.affiliation: Dept. of Medicine, Div. of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands.
authors.forename: Malou
authors.initials: M
authors.lastname: Crasborn
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands; Dept. of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Lianne
authors.initials: L
authors.lastname: van Beek
authors.affiliation: Dept. of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Susan M
authors.initials: SM
authors.lastname: van den Berg
authors.affiliation: Dept. of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Vrieling
authors.affiliation: Dept. of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Joosten
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands; Dept. of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Vanessa
authors.initials: V
authors.lastname: van Harmelen
authors.affiliation: Dept. of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Menno P J
authors.initials: MPJ
authors.lastname: de Winther
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Clinics Bonn, Bonn, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.affiliation: Dept. of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Prevention, Ludwig Maximilian's University Munich, Munich, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
authors.affiliation: Dept. of Medicine, Div. of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands.
authors.forename: Mariëtte R
authors.initials: MR
authors.lastname: Boon
authors.affiliation: Dept. of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Niels P
authors.initials: NP
authors.lastname: Riksen
authors.affiliation: Dept. of Medicine, Div. of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands.
authors.forename: Patrick C N
authors.initials: PCN
authors.lastname: Rensen
authors.affiliation: Dept. of Medicine, Div. of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands.
authors.forename: Jimmy F P
authors.initials: JFP
authors.lastname: Berbée
mesh_terms: D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood* / Q000628:therapy; D001500:BCG Vaccine / Q000627:therapeutic use*; D001823:Body Composition; D002784:Cholesterol / Q000097:blood* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005487:Foam Cells / Q000378:metabolism; D006949:Hyperlipidemias / Q000150:complications* / Q000473:pathology* / Q000628:therapy; D007107:Immune System; D007249:Inflammation / Q000628:therapy; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009163:Mycobacterium bovis; D010641:Phenotype
chemical_list: D053318:Apolipoprotein E3; D001500:BCG Vaccine; C052720:apolipoprotein E3 (Leidein); D002784:Cholesterol
keywords: Atherosclerosis; BCG; Hepatitis; Hypercholesterolemia