title: Disruption of the gene encoding 3beta-hydroxysterol Delta-reductase (Tm7sf2) in mice does not impair cholesterol biosynthesis.
abstract: Tm7sf2 gene encodes 3beta-hydroxysterol Delta(14)-reductase (C14SR, DHCR14), an endoplasmic reticulum enzyme acting on Delta(14)-unsaturated sterol intermediates during the conversion of lanosterol to cholesterol. The C-terminal domain of lamin B receptor, a protein of the inner nuclear membrane mainly involved in heterochromatin organization, also possesses sterol Delta(14)-reductase activity. The subcellular localization suggests a primary role of C14SR in cholesterol biosynthesis. To investigate the role of C14SR and lamin B receptor as 3beta-hydroxysterol Delta(14)-reductases, Tm7sf2 knockout mice were generated and their biochemical characterization was performed. No Tm7sf2 mRNA was detected in the liver of knockout mice. Neither C14SR protein nor 3beta-hydroxysterol Delta(14)-reductase activity were detectable in liver microsomes of Tm7sf2((-/-)) mice, confirming the effectiveness of gene inactivation. C14SR protein and its enzymatic activity were about half of control levels in the liver of heterozygous mice. Normal cholesterol levels in liver membranes and in plasma indicated that, despite the lack of C14SR, Tm7sf2((-/-)) mice are able to perform cholesterol biosynthesis. Lamin B receptor 3beta-hydroxysterol Delta(14)-reductase activity determined in liver nuclei showed comparable values in wild-type and knockout mice. These results suggest that lamin B receptor, although residing in nuclear membranes, may contribute to cholesterol biosynthesis in Tm7sf2((-/-)) mice. Affymetrix microarray analysis of gene expression revealed that several genes involved in cell-cycle progression are downregulated in the liver of Tm7sf2((-/-)) mice, whereas genes involved in xenobiotic metabolism are upregulated.
authors.affiliation: Department of Internal Medicine, University of Perugia, Italy.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Bennati
authors.forename: Gianluca
authors.initials: G
authors.lastname: Schiavoni
authors.forename: Sebastian
authors.initials: S
authors.lastname: Franken
authors.forename: Danilo
authors.initials: D
authors.lastname: Piobbico
authors.forename: Maria A
authors.initials: MA
authors.lastname: Della Fazia
authors.forename: Donatella
authors.initials: D
authors.lastname: Caruso
authors.forename: Emma
authors.initials: E
authors.lastname: De Fabiani
authors.forename: Laura
authors.initials: L
authors.lastname: Benedetti
authors.forename: Maria G
authors.initials: MG
authors.lastname: Cusella De Angelis
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gieselmann
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Servillo
authors.forename: Tommaso
authors.initials: T
authors.lastname: Beccari
authors.forename: Rita
authors.initials: R
authors.lastname: Roberti
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002784:Cholesterol / Q000096:biosynthesis*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008099:Liver; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver; D010088:Oxidoreductases / Q000235:genetics / Q000502:physiology*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D017474:Receptors, Laminin / Q000502:physiology*; D015262:Xenobiotics / Q000378:metabolism; D000097682:Lamin B Receptor
chemical_list: D002784:Cholesterol; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D018160:Receptors, Cytoplasmic and Nuclear; D017474:Receptors, Laminin; D015262:Xenobiotics; D000097682:Lamin B Receptor; C022672:delta(14)-sterol reductase