title: 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome.
abstract: Smith-Lemli-Opitz/RSH syndrome (SLOS), a relatively common birth-defect mental-retardation syndrome, is caused by mutations in DHCR7, whose product catalyzes an obligate step in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol. A null mutation in the murine Dhcr7 causes an identical biochemical defect to that seen in SLOS, including markedly reduced tissue cholesterol and total sterol levels, and 30- to 40-fold elevated concentrations of 7-dehydrocholesterol. Prenatal lethality was not noted, but newborn homozygotes breathed with difficulty, did not suckle, and died soon after birth with immature lungs, enlarged bladders, and, frequently, cleft palates. Despite reduced sterol concentrations in Dhcr7(-/-) mice, mRNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme for sterol biosynthesis, the LDL receptor, and SREBP-2 appeared neither elevated nor repressed. In contrast to mRNA, protein levels and activities of HMG-CoA reductase were markedly reduced. Consistent with this finding, 7-dehydrocholesterol accelerates proteolysis of HMG-CoA reductase while sparing other key proteins. These results demonstrate that in mice without Dhcr7 activity, accumulated 7-dehydrocholesterol suppresses sterol biosynthesis posttranslationally. This effect might exacerbate abnormal development in SLOS by increasing the fetal cholesterol deficiency.
authors.affiliation: Institute of Biochemical Pharmacology, Innsbruck, Austria.
authors.forename: B U
authors.initials: BU
authors.lastname: Fitzky
authors.forename: F F
authors.initials: FF
authors.lastname: Moebius
authors.forename: H
authors.initials: H
authors.lastname: Asaoka
authors.forename: H
authors.initials: H
authors.lastname: Waage-Baudet
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: G
authors.initials: G
authors.lastname: Xu
authors.forename: N
authors.initials: N
authors.lastname: Maeda
authors.forename: K
authors.initials: K
authors.lastname: Kluckman
authors.forename: S
authors.initials: S
authors.lastname: Hiller
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: A K
authors.initials: AK
authors.lastname: Batta
authors.forename: S
authors.initials: S
authors.lastname: Shefer
authors.forename: T
authors.initials: T
authors.lastname: Chen
authors.forename: G
authors.initials: G
authors.lastname: Salen
authors.forename: K
authors.initials: K
authors.lastname: Sulik
authors.forename: R D
authors.initials: RD
authors.lastname: Simoni
authors.forename: G C
authors.initials: GC
authors.lastname: Ness
authors.forename: H
authors.initials: H
authors.lastname: Glossmann
authors.forename: S B
authors.initials: SB
authors.lastname: Patel
authors.forename: G S
authors.initials: GS
authors.lastname: Tint
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004268:DNA-Binding Proteins / Q000235:genetics; D003684:Dehydrocholesterols / Q000378:metabolism*; D004195:Disease Models, Animal; D018390:Gene Targeting; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010088:Oxidoreductases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics; D044925:Oxidoreductases Acting on CH-CH Group Donors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols / Q000096:biosynthesis*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D003684:Dehydrocholesterols; D012333:RNA, Messenger; D011973:Receptors, LDL; C497390:SREBF2 protein, human; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols; D014157:Transcription Factors; C016705:7-dehydrocholesterol; D010088:Oxidoreductases; D006903:Hydroxymethylglutaryl CoA Reductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase