title: Studies on the cholesterol-free mouse: strong activation of LXR-regulated hepatic genes when replacing cholesterol with desmosterol.
abstract: OBJECTIVE
  Characterization of cholesterol homeostasis in male mice with a genetic inactivation of 3beta-hydroxysteroid-delta24-reductase, causing replacement of almost all cholesterol with desmosterol.
  
  
  RESULTS
  There was an increase in hepatic sterol synthesis and markedly increased fecal loss of neutral sterols. Fecal excretion of bile acids was similar in knockout mice and in controls. The composition of bile acids was changed, with reduced formation of cholic acid. It was shown that both Cyp7a1 and Cyp27a1 are active toward desmosterol, consistent with the formation of normal bile acids from this steroid. The levels of plant sterols were markedly reduced. Hepatic mRNA levels of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase, Srebp-1c, Srebp-2, Cyp7a1, Abcg5, Abcg8, and Fas were all significantly increased.
  
  
  CONCLUSIONS
  The changes in hepatic mRNA levels in combination with increased biliary and fecal excretion of neutral steroids, reduced tissue levels of plant sterols, increased plasma levels of triglyceride-rich VLDL, are consistent with a strong activation of LXR-targeted genes. The markedly increased fecal loss of neutral sterols may explain the fact that the Dhcr24-/- mice do not accumulate dietary cholesterol. The study illustrates the importance of the integrity of the cholesterol structure--presence of a double bond in the steroid side-chain is compatible with life but is associated with serious disturbances in sterol homeostasis.
authors.affiliation: Division of Clinical Chemistry, Karolinska University Hospital, Huddinge, S-14186, Sweden.
authors.forename: Maura
authors.initials: M
authors.lastname: Heverin
authors.forename: Steve
authors.initials: S
authors.lastname: Meaney
authors.forename: Anat
authors.initials: A
authors.lastname: Brafman
authors.forename: Millicent
authors.initials: M
authors.lastname: Shafir
authors.forename: Maria
authors.initials: M
authors.lastname: Olin
authors.forename: Marjan
authors.initials: M
authors.lastname: Shafaati
authors.forename: Sara
authors.initials: S
authors.lastname: von Bahr
authors.forename: Lilian
authors.initials: L
authors.lastname: Larsson
authors.forename: Anita
authors.initials: A
authors.lastname: Lövgren-Sandblom
authors.forename: Ulf
authors.initials: U
authors.lastname: Diczfalusy
authors.forename: Paolo
authors.initials: P
authors.lastname: Parini
authors.forename: Elena
authors.initials: E
authors.lastname: Feinstein
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000031:analogs & derivatives / Q000097:blood / Q000172:deficiency / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003897:Desmosterol / Q000097:blood / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation; D006706:Homeostasis; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D057093:Orphan Nuclear Receptors; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism*; D010840:Phytosterols / Q000097:blood / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: C462600:ABCG5 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D008055:Lipids; D008074:Lipoproteins; D000071518:Liver X Receptors; D009419:Nerve Tissue Proteins; D057093:Orphan Nuclear Receptors; D010840:Phytosterols; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D003897:Desmosterol; C028358:24,25-epoxycholesterol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499056:Dhcr24 protein, mouse