title: Carnitine deficiency in OCTN2-/- newborn mice leads to a severe gut and immune phenotype with widespread atrophy, apoptosis and a pro-inflammatory response.
abstract: We have investigated the gross, microscopic and molecular effects of carnitine deficiency in the neonatal gut using a mouse model with a loss-of-function mutation in the OCTN2 (SLC22A5) carnitine transporter. The tissue carnitine content of neonatal homozygous (OCTN2(-/-)) mouse small intestine was markedly reduced; the intestine displayed signs of stunted villous growth, early signs of inflammation, lymphocytic and macrophage infiltration and villous structure breakdown. Mitochondrial β-oxidation was active throughout the GI tract in wild type newborn mice as seen by expression of 6 key enzymes involved in β-oxidation of fatty acids and genes for these 6 enzymes were up-regulated in OCTN2(-/-) mice. There was increased apoptosis in gut samples from OCTN2(-/-) mice. OCTN2(-/-) mice developed a severe immune phenotype, where the thymus, spleen and lymph nodes became atrophied secondary to increased apoptosis. Carnitine deficiency led to 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 OCTN2(-/-) mouse gut epithelium demonstrated down-regulation of TGF-β/BMP pathway genes. We conclude that carnitine plays a major role in neonatal OCTN2(-/-) mouse gut development and differentiation, and that severe carnitine deficiency leads to increased apoptosis of enterocytes, villous atrophy, inflammation and gut injury.
authors.affiliation: Department of Pediatrics, Medical College of Georgia, Georgia Health Science University, Augusta, Georgia, United States of America.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Sonne
authors.forename: Prem S
authors.initials: PS
authors.lastname: Shekhawat
authors.forename: Dietrich
authors.initials: D
authors.lastname: Matern
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
authors.forename: Leszek
authors.initials: L
authors.lastname: Ignatowicz
mesh_terms: D000818:Animals; D017209:Apoptosis; D001284:Atrophy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D002331:Carnitine / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D015536:Down-Regulation; D020895:Enterocytes / Q000378:metabolism; D005260:Female; D041981:Gastrointestinal Tract / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D017353:Gene Deletion; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D010084:Oxidation-Reduction; D010641:Phenotype; D000074058:Solute Carrier Family 22 Member 5; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D019485:Bone Morphogenetic Proteins; D016207:Cytokines; D027701:Organic Cation Transport Proteins; C492019:Slc22a5 protein, mouse; D000074058:Solute Carrier Family 22 Member 5; D016212:Transforming Growth Factor beta; D002331:Carnitine