title: Sterol dependent regulation of human TM7SF2 gene expression: role of the encoded 3beta-hydroxysterol Delta14-reductase in human cholesterol biosynthesis.
abstract: 3Beta-hydroxysterol Delta(14)-reductase operates during the conversion of lanosterol to cholesterol in mammalian cells. Besides the endoplasmic reticulum 3beta-hydroxysterol Delta(14)-reductase (C14SR) encoded by TM7SF2 gene, the lamin B receptor (LBR) of the inner nuclear membrane possesses 3beta-hydroxysterol Delta(14)-reductase activity, based on its ability to complement C14SR-defective yeast strains. LBR was indicated as the primary 3beta-hydroxysterol Delta(14)-reductase in human cholesterol biosynthesis, since mutations in LBR gene were found in Greenberg skeletal dysplasia, characterized by accumulation of Delta(14)-unsaturated sterols. This study addresses the issue of C14SR and LBR role in cholesterol biosynthesis. Both human C14SR and LBR expressed in COS-1 cells exhibit 3beta-hydroxysterol Delta(14)-reductase activity in vitro. TM7SF2 mRNA and C14SR protein expression in HepG2 cells grown in delipidated serum (LPDS) plus lovastatin (sterol starvation) were 4- and 8-fold higher, respectively, than in LPDS plus 25-hydroxycholesterol (sterol feeding), resulting in 4-fold higher 3beta-hydroxysterol Delta(14)-reductase activity. No variations in LBR mRNA and protein levels were detected in the same conditions. The induction of TM7SF2 gene expression is turned-on by promoter activation in response to low cell sterol levels and is mediated by SREBP-2. The results suggest a primary role of C14SR in human cholesterol biosynthesis, whereas LBR role in the pathway remains unclear.
authors.affiliation: Department of Internal Medicine, Laboratory of Biochemistry, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Bennati
authors.forename: Marilena
authors.initials: M
authors.lastname: Castelli
authors.forename: Maria Agnese
authors.initials: MA
authors.lastname: Della Fazia
authors.forename: Tommaso
authors.initials: T
authors.lastname: Beccari
authors.forename: Donatella
authors.initials: D
authors.lastname: Caruso
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Servillo
authors.forename: Rita
authors.initials: R
authors.lastname: Roberti
mesh_terms: D001848:Bone Diseases, Developmental / Q000201:enzymology / Q000235:genetics; D002784:Cholesterol / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D000097682:Lamin B Receptor
chemical_list: D002784:Cholesterol; D006888:Hydroxycholesterols; D008148:Lovastatin; D008565:Membrane Proteins; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D018160:Receptors, Cytoplasmic and Nuclear; D051782:Sterol Regulatory Element Binding Protein 2; D000097682:Lamin B Receptor; C497390:SREBF2 protein, human; C007997:25-hydroxycholesterol; C113387:TM7SF2 protein, human; C022672:delta(14)-sterol reductase