title: Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis.
abstract: Mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) are the principal cause of Rett syndrome, a progressive neurodevelopmental disorder afflicting 1 in 10,000 to 15,000 females. Studies using hemizygous Mecp2 mouse models have revealed disruptions to some aspects of their lipid metabolism including a partial suppression of cholesterol synthesis in the brains of mature Mecp2 mutants. The present studies investigated whether this suppression is evident from early neonatal life, or becomes manifest at a later stage of development. We measured the rate of cholesterol synthesis, in vivo, in the brains of male Mecp2-/yand their Mecp2+/ylittermates at 7, 14, 21, 28, 42 and 56 days of age. Brain weight was consistently lower in the Mecp2-/ymice than in their Mecp2+/ycontrols except at 7 days of age. In the 7- and 14-day-old mice there was no genotypic difference in the rate of brain cholesterol synthesis but, from 21 days and later, it was always marginally lower in the Mecp2-/ymice than in age-matched Mecp2+/ylittermates. At no age was a genotypic difference detected in either the rate of fatty acid synthesis or cholesterol concentration in the brain. Cholesterol synthesis rates in the liver and lungs of 56-day-old Mecp2-/ymice were normal. The onset of lower rates of brain cholesterol synthesis at about the time closure of the blood brain barrier purportedly occurs might signify a disruption to mechanism(s) that dictate intracellular levels of cholesterol metabolites including oxysterols known to exert a regulatory influence on the cholesterol biosynthetic pathway.
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: adam.lopez@utsouthwestern.edu.
authors: Adam M
authors: AM
authors: Lopez
authors: Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: Jen-Chieh.Chuang@gilead.com.
authors: Jen-Chieh
authors: JC
authors: Chuang
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: kennethsposey@gmail.com.
authors: Kenneth S
authors: KS
authors: Posey
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: stephen.turley@utsouthwestern.edu.
authors: Stephen D
authors: SD
authors: Turley
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000096:biosynthesis*; D000072556:Cholesterol 24-Hydroxylase / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D008099:Liver / Q000254:growth & development / Q000378:metabolism; D008168:Lung / Q000254:growth & development / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency* / Q000235:genetics; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size; D012333:RNA, Messenger
chemical_list: D001057:Apolipoproteins E; D005227:Fatty Acids; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D012333:RNA, Messenger; D002784:Cholesterol; D000072556:Cholesterol 24-Hydroxylase
keywords: Brain weight; Desmosterol; Fatty acid synthesis; Ontogeny; Rett syndrome