Faculty Collaboration Database

7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome. J Clin Invest 2001 Sep;108(6):905-15

Date

09/19/2001

Pubmed ID

11560960

Pubmed Central ID

PMC200927

DOI

10.1172/JCI12103

Scopus ID

2-s2.0-0034829757 (requires institutional sign-in at Scopus site)   150 Citations

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.

Author List

Fitzky BU, Moebius FF, Asaoka H, Waage-Baudet H, Xu L, Xu G, Maeda N, Kluckman K, Hiller S, Yu H, Batta AK, Shefer S, Chen T, Salen G, Sulik K, Simoni RD, Ness GC, Glossmann H, Patel SB, Tint GS

Author

Hongwei Yu MD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
DNA-Binding Proteins
Dehydrocholesterols
Disease Models, Animal
Gene Targeting
Humans
Hydroxymethylglutaryl CoA Reductases
Mice
Mice, Knockout
Oxidoreductases
Oxidoreductases Acting on CH-CH Group Donors
RNA, Messenger
Receptors, LDL
Smith-Lemli-Opitz Syndrome
Sterol Regulatory Element Binding Protein 2
Sterols
Transcription Factors