Carnitine Deficiency in OCTN2？？ Newborn Mice Leads to a Severe Gut and Immune Phenotype with Widespread Atrophy, Apoptosis and a Pro-Inflammatory Response 英文参考文献.docVIP

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Carnitine Deficiency in OCTN2？？ Newborn Mice Leads to a Severe Gut and Immune Phenotype with Widespread Atrophy, Apoptosis and a Pro-Inflammatory Response 英文参考文献.doc

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Carnitine Deficiency in OCTN2？？ Newborn Mice Leads to a Severe Gut and Immune Phenotype with Widespread Atrophy, Apoptosis and a Pro-Inflammatory Response 英文参考文献

CarnitineDeficiencyinOCTN22/2 NewbornMiceLeads toaSevereGutandImmunePhenotypewith WidespreadAtrophy,ApoptosisandaPro-Inflammatory Response SrinivasSonne1,2,PremS.Shekhawat1,2*,DietrichMatern3,VadivelGanapathy2,LeszekIgnatowicz4 1DepartmentofPediatrics,MedicalCollegeofGeorgia,GeorgiaHealthScienceUniversity,Augusta,Georgia,UnitedStatesofAmerica,2DepartmentofBiochemistryand MolecularBiology,MedicalCollegeofGeorgia,GeorgiaHealthSciencesUniversity,Augusta,Georgia,UnitedStatesofAmerica,3DepartmentsofLaboratoryMedicine Pathology, Medical Genetics, and Pediatric Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America, 4Center for BiotechnologyandGenomicMedicine,MedicalCollegeofGeorgia,GeorgiaHealthSciencesUniversity,Augusta,Georgia,UnitedStatesofAmerica Abstract Wehaveinvestigatedthegross,microscopicandmoleculareffectsofcarnitinedeficiencyintheneonatalgutusingamouse model with a loss-of-function mutation in the OCTN2 (SLC22A5) carnitine transporter. The tissue carnitine content of neonatalhomozygous(OCTN22/2)mousesmallintestinewasmarkedlyreduced;theintestinedisplayedsignsofstunted villous growth, early signs of inflammation, lymphocytic and macrophage infiltration and villous structure breakdown. Mitochondrialb-oxidationwasactivethroughouttheGItractinwildtypenewbornmiceasseenbyexpressionof6key enzymesinvolvedinb-oxidationoffattyacidsandgenesforthese6enzymeswereup-regulatedinOCTN22/2mice.There was increased apoptosis in gutsamples fromOCTN22/2 mice. OCTN22/2 mice developedasevere immune phenotype, wherethethymus,spleenandlymphnodesbecameatrophiedsecondarytoincreasedapoptosis.Carnitinedeficiencyledto increased expression of CD45-B220+ lymphocytes with increased production of basal and anti-CD3-stimulated pro- inflammatory cytokines in immune cells. Real-time PCR array analysis in OCTN22/2 mouse gutepithelium demonstrated down-regulationofTGF-b/BMPpathwaygenes.WeconcludethatcarnitineplaysamajorroleinneonatalOCTN22/2mouse gut dev