Carnitine Deficiency in OCTN2-/- Newborn Mice Leads to a Severe Gut and Immune Phenotype with Widespread Atrophy, Apoptosis and a Pro-Inflammatory Response

Srinivas Sonne, Prem S. Shekhawat, Dietrich Matern, Vadivel Ganapathy, Leszek Ignatowicz

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere47729
JournalPloS one
Volume7
Issue number10
DOIs
StatePublished - Oct 24 2012

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Carnitine
carnitine
atrophy
Atrophy
neonates
apoptosis
digestive system
inflammation
Apoptosis
Phenotype
phenotype
mice
Genes
Thymus
Oxidation
beta oxidation
Lymphocytes
Macrophages
enterocytes
Growth Disorders

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Carnitine Deficiency in OCTN2-/- Newborn Mice Leads to a Severe Gut and Immune Phenotype with Widespread Atrophy, Apoptosis and a Pro-Inflammatory Response. / Sonne, Srinivas; Shekhawat, Prem S.; Matern, Dietrich; Ganapathy, Vadivel; Ignatowicz, Leszek.

In: PloS one, Vol. 7, No. 10, e47729, 24.10.2012.

Research output: Contribution to journalArticle

Sonne, Srinivas ; Shekhawat, Prem S. ; Matern, Dietrich ; Ganapathy, Vadivel ; Ignatowicz, Leszek. / Carnitine Deficiency in OCTN2-/- Newborn Mice Leads to a Severe Gut and Immune Phenotype with Widespread Atrophy, Apoptosis and a Pro-Inflammatory Response. In: PloS one. 2012 ; Vol. 7, No. 10.
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