Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice.

Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice. Research Abstract Details 

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Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice. Abstract Text:

Hongwei Yu,Man Li,G Stephen Tint,Jianliang Chen,Guorong Xu,Shailendra B Patel,

BACKGROUND: Targeted disruption of the murine 3beta-hydroxysterol-Delta7-reductase gene (Dhcr7), an animal model of Smith-Lemli-Opitz syndrome, leads to loss of cholesterol synthesis and neonatal death that can be partially rescued by transgenic replacement of DHCR7 expression in brain during embryogenesis. To gain further insight into the role of non-brain tissue cholesterol deficiency in the pathophysiology, we tested whether the lethal phenotype could be abrogated by selective transgenic complementation with DHCR7 expression in the liver. RESULTS: We generated mice that carried a liver-specific human DHCR7 transgene whose expression was driven by the human apolipoprotein E (ApoE) promoter and its associated liver-specific enhancer. These mice were then crossed with Dhcr7+/- mutants to generate Dhcr7-/- mice bearing a human DHCR7 transgene. Robust hepatic transgene expression resulted in significant improvement of cholesterol homeostasis with cholesterol concentrations increasing to 80~90 % of normal levels in liver and lung. Significantly, cholesterol deficiency in brain was not altered. Although late gestational lung sacculation defect reported previously was significantly improved, there was no parallel increase in postnatal survival in the transgenic mutant mice. CONCLUSION: The reconstitution of DHCR7 function selectively in liver induced a significant improvement of cholesterol homeostasis in non-brain tissues, but failed to rescue the neonatal lethality of Dhcr7 null mice. These results provided further evidence that CNS defects caused by Dhcr7 null likely play a major role in the lethal pathogenesis of Dhcr7-/- mice, with the peripheral organs contributing the morbidity.

Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice. Publishing Authors By Initials

H Yu,M Li,GS Tint,J Chen,G Xu,SB Patel,

For similar genetic structures: genome: genome components: genes: transgenes research abstracts see: genetic structures: genome: genome components: genes: transgenes research

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Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: BMC developmental biology

VOLUME: 7

Page Numbers: 27

Journal Abbreviation:

ISSN: 1471-213X

DAY: 4

MONTH: 04

YEAR: 2007

Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice. Information

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LANGUAGE: eng

NlmUniqueID: 100966973

Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice. Keywords Mesh Terms:

KEYWORDS: Transgenes

MESH TERMS: genetics

Chemical & Substance for Abstract: Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice. Information

Substance Name: 7-dehydrocholesterol reductase

Registry Number: EC 1.3.1.21

Grant and Affiliation Information for Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice.

AFFILIATION: Division of Endocrinology, Metabolism and Nutrition, Medical College of Wisconsin, Milwaukee, WI 53226, USA. hyu@mcw.edu

Country: England

AGENCY: United States NHLBI

GRANT: HL68660

ACRONYM: HL

MEDLINETA: BMC Dev Biol

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