title: Selective reconstitution of liver cholesterol biosynthesis promotes lung maturation but does not prevent neonatal lethality in Dhcr7 null mice.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Endocrinology, Metabolism and Nutrition, Medical College of Wisconsin, Milwaukee, WI 53226, USA. hyu@mcw.edu
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yu
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.forename: G Stephen
authors.initials: GS
authors.lastname: Tint
authors.forename: Jianliang
authors.initials: J
authors.lastname: Chen
authors.forename: Guorong
authors.initials: G
authors.lastname: Xu
authors.forename: Shailendra B
authors.initials: SB
authors.lastname: Patel
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001057:Apolipoproteins E / Q000235:genetics; D002784:Cholesterol / Q000096:biosynthesis*; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D005325:Fetal Organ Maturity; D006801:Humans; D008099:Liver / Q000196:embryology / Q000378:metabolism*; D008168:Lung / Q000196:embryology*; D008297:Male; D021962:Membrane Microdomains / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency / Q000235:genetics*; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics; D019076:Transgenes
chemical_list: D001057:Apolipoproteins E; D017931:DNA Primers; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase