title: Hematopoietic overexpression of Cyp27a1 reduces hepatic inflammation independently of 27-hydroxycholesterol levels in Ldlr(-/-) mice.
abstract: OBJECTIVE
  Non-alcoholic steatohepatitis (NASH) is characterized by hepatic lipid accumulation and inflammation. Currently, the underlying mechanisms, leading to hepatic inflammation, are still unknown. The breakdown of free cholesterol inside Kupffer cells (KCs) by the mitochondrial enzyme CYP27A1 produces 27-hydroxycholesterol (27HC). We recently demonstrated that administration of 27HC to hyperlipidemic mice reduced hepatic inflammation. In line, hematopoietic deletion of Cyp27a1 resulted in increased hepatic inflammation. In the current manuscript, the effect of hematopoietic overexpression of Cyp27a1 on the development of NASH and cholesterol trafficking was investigated. We hypothesized that Cyp27a1 overexpression in KCs will lead to reduced hepatic inflammation.
  
  
  METHODS
  Irradiated Ldlr(-/-) mice were transplanted (tp) with bone marrow from mice overexpressing Cyp27a1 (Cyp27a1(over)) and wild type (Wt) mice and fed either chow or a high-fat, high-cholesterol (HFC) diet for 3 months. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) from Cyp27a1(over) and Wt mice.
  
  
  RESULTS
  In line with our hypothesis, hepatic inflammation in HFC-fed Cyp27a1(over)-tp mice was reduced and KCs were less foamy compared to Wt-tp mice. Remarkably, these changes occurred even though plasma and liver levels of 27HC did not differ between both groups. BMDM from Cyp27a1(over) mice revealed reduced inflammatory gene expression and increased expression of cholesterol transporters compared to Wt BMDM after lipopolysaccharide (LPS) stimulation.
  
  
  CONCLUSIONS
  Our data suggest that overexpression of Cyp27a1 in KCs reduces hepatic inflammation independently of 27HC levels in plasma and liver, further pointing towards KCs as specific target for improving the therapy of NASH.
authors.affiliation: Department of Molecular Genetics, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands; Department of Molecular Cell Biology, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Hendrikx
authors.affiliation: Department of Molecular Genetics, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands; Department of Molecular Cell Biology, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Mike L J
authors.initials: ML
authors.lastname: Jeurissen
authors.affiliation: Department of Molecular Genetics, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands; Department of Molecular Cell Biology, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Veerle
authors.initials: V
authors.lastname: Bieghs
authors.affiliation: Department of Molecular Genetics, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands; Department of Molecular Cell Biology, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Sofie M A
authors.initials: SM
authors.lastname: Walenbergh
authors.affiliation: Department of Molecular Genetics, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands; Department of Molecular Cell Biology, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: van Gorp
authors.affiliation: Department of Molecular Genetics, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands; Department of Molecular Cell Biology, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Fons
authors.initials: F
authors.lastname: Verheyen
authors.affiliation: Department of Molecular Genetics, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands; Department of Molecular Cell Biology, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Houben
authors.affiliation: Department of Molecular Genetics, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands; Department of Molecular Cell Biology, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Yasmin Dias
authors.initials: YD
authors.lastname: Guichot
authors.affiliation: Department of Molecular Genetics, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands; Department of Molecular Cell Biology, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Marion J J
authors.initials: MJ
authors.lastname: Gijbels
authors.affiliation: Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Leitersdorf
authors.affiliation: Department of Pathology & Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.affiliation: Department of Molecular Genetics, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands; Department of Molecular Cell Biology, ELMI Unit (CRISP) and Pathology, Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM), Institutes of Maastricht, University of Maastricht, Maastricht, The Netherlands. Electronic address: r.sverdlov@maastrichtuniversity.nl.
authors.forename: Ronit
authors.initials: R
authors.lastname: Shiri-Sverdlov
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D053493:Cholestanetriol 26-Monooxygenase / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006888:Hydroxycholesterols / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D006888:Hydroxycholesterols; D008077:Lipoproteins, LDL; C076996:27-hydroxycholesterol; D004247:DNA; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse
keywords: CYP27A1; Cholesterol; Hepatic inflammation; Kupffer cells