title: The cholesterol derivative 27-hydroxycholesterol reduces steatohepatitis in mice.
abstract: OBJECTIVE
  Non-alcoholic steatohepatitis is characterized by hepatic steatosis with inflammation. Although steatosis is benign and reversible, inflammation can increase liver damage. Hepatic inflammation has been associated with accumulation of cholesterol in lysosomes of Kupffer cells. 27-Hydroxycholesterol (27HC), a derivative of cholesterol formed by CYP27A1, can mobilize cholesterol from the lysosomes to the cytoplasm. We investigated whether 27HC can change the intracellular distribution cholesterol and reduce hepatic inflammation in mice.
  
  
  METHODS
  We transplanted bone marrow from irradiated wild-type or Cyp27a1(-/-) mice to mice that do not express the low density lipoprotein receptor (Ldlr(-/-)), which are hyperlipidemic; 9 weeks later, mice were fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 3 months. In a separate experiment, Ldlr(-/-) mice were given subcutaneous injections of 27HC and placed on regular chow or HFC diets for 3 weeks. Blood and liver tissues samples were collected and analyzed for intracellular cholesterol distribution and inflammation.
  
  
  RESULTS
  In Ldlr(-/-) mice that received bone marrow transplants from Cyp27a1(-/-) mice, lysosomes of Kupfer cells had a greater accumulation of cholesterol than those of mice that received bone marrow from wild-type mice, after the HFC diet. Liver histology and gene expression analyses showed increased inflammation and liver damage in mice given bone marrow transplants from Cyp27a1(-/-) mice and placed on the HFC diet. Administration of 27HC to Ldlr(-/-) mice, following the HFC diet, reduced the accumulation of lysosomal cholesterol and hepatic inflammation, compared with mice that were not given 27HC.
  
  
  CONCLUSIONS
  Accumulation of cholesterol in lysosomes of Kupfer cells promotes hepatic inflammation in mice. The cholesterol derivative 27HC reduces accumulation of cholesterol in lysosomes and might be used to treat non-alcoholic steatohepatitis.
authors.affiliation: Department of Molecular Genetics, Maastricht University, Maastricht, the Netherlands.
authors.forename: Veerle
authors.initials: V
authors.lastname: Bieghs
authors.forename: Tim
authors.initials: T
authors.lastname: Hendrikx
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: van Gorp
authors.forename: Fons
authors.initials: F
authors.lastname: Verheyen
authors.forename: Yasmin Dias
authors.initials: YD
authors.lastname: Guichot
authors.forename: Sofie M A
authors.initials: SM
authors.lastname: Walenbergh
authors.forename: Mike L J
authors.initials: ML
authors.lastname: Jeurissen
authors.forename: Marion
authors.initials: M
authors.lastname: Gijbels
authors.forename: Sander S
authors.initials: SS
authors.lastname: Rensen
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
authors.forename: Jogchum
authors.initials: J
authors.lastname: Plat
authors.forename: Satish C
authors.initials: SC
authors.lastname: Kalhan
authors.forename: Ger H
authors.initials: GH
authors.lastname: Koek
authors.forename: Eran
authors.initials: E
authors.lastname: Leitersdorf
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Ronit
authors.initials: R
authors.lastname: Shiri-Sverdlov
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D016026:Bone Marrow Transplantation; D053493:Cholestanetriol 26-Monooxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage; D005234:Fatty Liver / Q000150:complications; D005260:Female; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006505:Hepatitis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D057093:Orphan Nuclear Receptors / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000410:Alanine Transaminase; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D053493:Cholestanetriol 26-Monooxygenase; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D006888:Hydroxycholesterols; D008055:Lipids; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; C487540:ABCG1 protein, mouse; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C497388:Srebf1 protein, mouse; C076996:27-hydroxycholesterol; C506832:Cyp27a1 protein, mouse