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.

Changes in mRNA Expression Levels of Solute Carrier Transporters in Inflammatory Bowel Disease Patients

“…It has been reported that SLC22A genes are high susceptibility genes in IBD, located at the so-called IBD locus 5 (IBD5) and that genetic polymorphisms within this region contribute to the inflammatory phenotype (Waller et al, 2006;Cucchiara et al, 2007;Silverberg et al, 2007). These observations are consistent with a mouse study showing that homozygous inactivation of Octn2 resulted in spontaneous development of colitis (Shekhawat et al, 2007). Decreased expression levels of Octn2 and another carnitine transporter Atb0ϩ were also shown to be associated with development of an inflammatory condition in rats (D'Argenio et al, 2006).…”

“…The OCTN2 protein is encoded by the IBD5 locus and polymorphisms in the SLC22A5 coding regions have been linked to IBD pathology (Russell et al, Waller et al, 2006;Cucchiara et al, 2007;Silverberg et al, 2007). In rats, a decrease in Octn2 expression levels triggers inflammation of the gastrointestinal tract (Shekhawat et al, 2007), possibly due to an aberration of carnitine transport and fatty acid metabolism (D'Argenio et al, 2006). It is interesting to note that a decrease in mRNA expression of OCTN2 was recently reported in the sigmoid region of UC colon (Noble et al, 2008), although to a lesser extent than to the decrease observed here in colon and terminal ileum (Table 3).…”

Gene Knockout and Metabolome Analysis of Carnitine/Organic Cation Transporter OCTN1

“…This idea is supported by recent findings of spontaneous development of intestinal atrophy and inflammation in jvs mice, demonstrating an obligatory role of OCTN2 in the maintenance of normal intestinal morphology (11).…”

GUT IMMUNITY IN BIRDS: FACTS AND REFLECTIONS (review)

“…This substance showed a strong protective effect in gastric disorders of rats (152). As found in mice deficient in specific carnitine transporters, the lack of carnitine leads to spontaneous atrophy of epithelial cells in the small intestine and colon inflammation (153). In old rats, dietary administration of carnitine for 21 days contributed to significant reduce in formation of LPO products and improved activity of antioxidant enzymes -superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase.…”