Sterol dependent regulation of human TM7SF2 gene expression: role of the encoded 3beta-hydroxysterol Delta14-reductase in human cholesterol biosynthesis.
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.
Bennati
Anna Maria
AM
Department of Internal Medicine, Laboratory of Biochemistry, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.
Castelli
Marilena
M
Della Fazia
Maria Agnese
MA
Beccari
Tommaso
T
Caruso
Donatella
D
Servillo
Giuseppe
G
Roberti
Rita
R
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
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