Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2-/-) mice

Prem S. Shekhawat, Sonne R. Srinivas, Dietrich Matern, Michael J. Bennett, Richard Boriack, Varghese George, Hongyan Xu, Puttur D Prasad, Penny Roon, Vadivel Ganapathy

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Carnitine is essential for transport of long-chain fatty acids into mitochondria for their subsequent β-oxidation, but its role in the gastrointestinal tract has not been well described. Recently several genetic epidemiologic studies have shown strong association between mutations in carnitine transporter genes OCTN1 and OCTN2 and a propensity to develop Crohn's disease. This study aims to investigate role of carnitine and β-oxidation in the GI tract. We have studied the gastrointestinal tract effects of carnitine deficiency in a mouse model with loss-of-function mutation in the OCTN2 carnitine transporter. juvenile visceral steatosis (OCTN2-/-) mouse spontaneously develops intestinal villous atrophy, breakdown and inflammation with intense lymphocytic and macrophage infiltration, leading to ulcer formation and gut perforation. There is increased apoptosis of jvs (OCTN2-/-) gut epithelial cells. We observed an up-regulation of heat shock factor-1 (HSF-1) and several heat shock proteins (HSPs) which are known to regulate OCTN2 gene expression. Intestinal and colonic epithelial cells in wild type mice showed high expression and activity of the enzymes of β-oxidation pathway. These studies provide evidence of an obligatory role for carnitine in the maintenance of normal intestinal and colonic structure and morphology. Fatty acid oxidation, a metabolic pathway regulated by carnitine-dependent entry of long-chain fatty acids into mitochondrial matrix, is likely essential for normal gut function. Our studies suggest that carnitine supplementation, as a means of boosting fatty acid oxidation, may be therapeutically beneficial in patients with inflammation of the intestinal tract.

Original languageEnglish (US)
Pages (from-to)315-324
Number of pages10
JournalMolecular Genetics and Metabolism
Volume92
Issue number4
DOIs
StatePublished - Dec 1 2007

Fingerprint

Carnitine
Atrophy
Inflammation
Fatty Acids
Oxidation
Gastrointestinal Tract
Epithelial Cells
Mutation
Mitochondria
Macrophages
Fatty Liver
Heat-Shock Proteins
Metabolic Networks and Pathways
Infiltration
Gene expression
Crohn Disease
Ulcer
Epidemiologic Studies
Shock
Up-Regulation

Keywords

  • Carnitine
  • Crohn's disease
  • Fatty acid β-oxidation
  • Inflammation
  • NEC

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2-/-) mice. / Shekhawat, Prem S.; Srinivas, Sonne R.; Matern, Dietrich; Bennett, Michael J.; Boriack, Richard; George, Varghese; Xu, Hongyan; Prasad, Puttur D; Roon, Penny; Ganapathy, Vadivel.

In: Molecular Genetics and Metabolism, Vol. 92, No. 4, 01.12.2007, p. 315-324.

Research output: Contribution to journalArticle

Shekhawat, Prem S. ; Srinivas, Sonne R. ; Matern, Dietrich ; Bennett, Michael J. ; Boriack, Richard ; George, Varghese ; Xu, Hongyan ; Prasad, Puttur D ; Roon, Penny ; Ganapathy, Vadivel. / Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2-/-) mice. In: Molecular Genetics and Metabolism. 2007 ; Vol. 92, No. 4. pp. 315-324.
@article{f5e64538204b44899af512e6c105eccc,
title = "Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2-/-) mice",
abstract = "Carnitine is essential for transport of long-chain fatty acids into mitochondria for their subsequent β-oxidation, but its role in the gastrointestinal tract has not been well described. Recently several genetic epidemiologic studies have shown strong association between mutations in carnitine transporter genes OCTN1 and OCTN2 and a propensity to develop Crohn's disease. This study aims to investigate role of carnitine and β-oxidation in the GI tract. We have studied the gastrointestinal tract effects of carnitine deficiency in a mouse model with loss-of-function mutation in the OCTN2 carnitine transporter. juvenile visceral steatosis (OCTN2-/-) mouse spontaneously develops intestinal villous atrophy, breakdown and inflammation with intense lymphocytic and macrophage infiltration, leading to ulcer formation and gut perforation. There is increased apoptosis of jvs (OCTN2-/-) gut epithelial cells. We observed an up-regulation of heat shock factor-1 (HSF-1) and several heat shock proteins (HSPs) which are known to regulate OCTN2 gene expression. Intestinal and colonic epithelial cells in wild type mice showed high expression and activity of the enzymes of β-oxidation pathway. These studies provide evidence of an obligatory role for carnitine in the maintenance of normal intestinal and colonic structure and morphology. Fatty acid oxidation, a metabolic pathway regulated by carnitine-dependent entry of long-chain fatty acids into mitochondrial matrix, is likely essential for normal gut function. Our studies suggest that carnitine supplementation, as a means of boosting fatty acid oxidation, may be therapeutically beneficial in patients with inflammation of the intestinal tract.",
keywords = "Carnitine, Crohn's disease, Fatty acid β-oxidation, Inflammation, NEC",
author = "Shekhawat, {Prem S.} and Srinivas, {Sonne R.} and Dietrich Matern and Bennett, {Michael J.} and Richard Boriack and Varghese George and Hongyan Xu and Prasad, {Puttur D} and Penny Roon and Vadivel Ganapathy",
year = "2007",
month = "12",
day = "1",
doi = "10.1016/j.ymgme.2007.08.002",
language = "English (US)",
volume = "92",
pages = "315--324",
journal = "Molecular Genetics and Metabolism",
issn = "1096-7192",
publisher = "Academic Press Inc.",
number = "4",

}

TY - JOUR

T1 - Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2-/-) mice

AU - Shekhawat, Prem S.

AU - Srinivas, Sonne R.

AU - Matern, Dietrich

AU - Bennett, Michael J.

AU - Boriack, Richard

AU - George, Varghese

AU - Xu, Hongyan

AU - Prasad, Puttur D

AU - Roon, Penny

AU - Ganapathy, Vadivel

PY - 2007/12/1

Y1 - 2007/12/1

N2 - Carnitine is essential for transport of long-chain fatty acids into mitochondria for their subsequent β-oxidation, but its role in the gastrointestinal tract has not been well described. Recently several genetic epidemiologic studies have shown strong association between mutations in carnitine transporter genes OCTN1 and OCTN2 and a propensity to develop Crohn's disease. This study aims to investigate role of carnitine and β-oxidation in the GI tract. We have studied the gastrointestinal tract effects of carnitine deficiency in a mouse model with loss-of-function mutation in the OCTN2 carnitine transporter. juvenile visceral steatosis (OCTN2-/-) mouse spontaneously develops intestinal villous atrophy, breakdown and inflammation with intense lymphocytic and macrophage infiltration, leading to ulcer formation and gut perforation. There is increased apoptosis of jvs (OCTN2-/-) gut epithelial cells. We observed an up-regulation of heat shock factor-1 (HSF-1) and several heat shock proteins (HSPs) which are known to regulate OCTN2 gene expression. Intestinal and colonic epithelial cells in wild type mice showed high expression and activity of the enzymes of β-oxidation pathway. These studies provide evidence of an obligatory role for carnitine in the maintenance of normal intestinal and colonic structure and morphology. Fatty acid oxidation, a metabolic pathway regulated by carnitine-dependent entry of long-chain fatty acids into mitochondrial matrix, is likely essential for normal gut function. Our studies suggest that carnitine supplementation, as a means of boosting fatty acid oxidation, may be therapeutically beneficial in patients with inflammation of the intestinal tract.

AB - Carnitine is essential for transport of long-chain fatty acids into mitochondria for their subsequent β-oxidation, but its role in the gastrointestinal tract has not been well described. Recently several genetic epidemiologic studies have shown strong association between mutations in carnitine transporter genes OCTN1 and OCTN2 and a propensity to develop Crohn's disease. This study aims to investigate role of carnitine and β-oxidation in the GI tract. We have studied the gastrointestinal tract effects of carnitine deficiency in a mouse model with loss-of-function mutation in the OCTN2 carnitine transporter. juvenile visceral steatosis (OCTN2-/-) mouse spontaneously develops intestinal villous atrophy, breakdown and inflammation with intense lymphocytic and macrophage infiltration, leading to ulcer formation and gut perforation. There is increased apoptosis of jvs (OCTN2-/-) gut epithelial cells. We observed an up-regulation of heat shock factor-1 (HSF-1) and several heat shock proteins (HSPs) which are known to regulate OCTN2 gene expression. Intestinal and colonic epithelial cells in wild type mice showed high expression and activity of the enzymes of β-oxidation pathway. These studies provide evidence of an obligatory role for carnitine in the maintenance of normal intestinal and colonic structure and morphology. Fatty acid oxidation, a metabolic pathway regulated by carnitine-dependent entry of long-chain fatty acids into mitochondrial matrix, is likely essential for normal gut function. Our studies suggest that carnitine supplementation, as a means of boosting fatty acid oxidation, may be therapeutically beneficial in patients with inflammation of the intestinal tract.

KW - Carnitine

KW - Crohn's disease

KW - Fatty acid β-oxidation

KW - Inflammation

KW - NEC

UR - http://www.scopus.com/inward/record.url?scp=36248946755&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36248946755&partnerID=8YFLogxK

U2 - 10.1016/j.ymgme.2007.08.002

DO - 10.1016/j.ymgme.2007.08.002

M3 - Article

C2 - 17884651

AN - SCOPUS:36248946755

VL - 92

SP - 315

EP - 324

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

SN - 1096-7192

IS - 4

ER -