OCTN1 variant L503F is associated with familial and sporadic inflammatory bowel disease

Lin, Zhenwu; Nelson, L; Franke, André; Poritz, Lisa S.; Li, Tong Yi; Wu, Rongling; Wang, Yunhua; MacNeill, Colin; Thomas, Neal J.; Schreiber, Stefan; Koltun, Walter A.

doi:10.1016/j.crohns.2009.09.003

Cited by 22 publications

(18 citation statements)

References 43 publications

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“…In addition, they found that the haplotype consisting of L503F of OCTN1 and g.-207G>C of OCTN2 was significantly associated with susceptibility to Crohn's disease. This finding was validated in subsequent studies [9,10,11,12,13,14]. …”

Section: Introductionsupporting

confidence: 73%

“…Many previous studies reported that a missense variant of OCTN1 is associated with the susceptibility to, or progression of, human diseases, particularly Crohn's disease [8,9,10,11,12,13,14,15]. For example, Peltekova et al [8] demonstrated that L503F of OCTN1 showed increased transport activity for TEA while it had decreased transport activity for other endogenous compounds including carnitine through in vitro uptake assay.…”

Section: Introductionmentioning

confidence: 99%

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Identification and Functional Characterization of Novel Genetic Variations in theOCTN1Promoter

Park

Choi

2014

Korean J Physiol Pharmacol

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Human organic cation/carnitine transporter 1 (OCTN1) plays an important role in the transport of drugs and endogenous substances. It is known that a missense variant of OCTN1 is significantly associated with Crohn's disease susceptibility. This study was performed to identify genetic variants of the OCTN1 promoter in Korean individuals and to determine their functional effects. First, the promoter region of OCTN1 was directly sequenced using genomic DNA samples from 48 healthy Koreans. OCTN1 promoter activity was then measured using a luciferase reporter assay in HCT-116 cells. Seven variants of the OCTN1 promoter were identified, two of which were novel. There were also four major OCTN1 promoter haplotypes. Three haplotypes (H1, H3, and H4) showed decreased transcriptional activity, which was reduced by 22.9%, 23.0%, and 44.6%, respectively (p<0.001), compared with the reference haplotype (H2). Transcription factor binding site analyses and gel shift assays revealed that NF-Y could bind to the region containing g.-1875T>A, a variant present in H3, and that the binding affinity of NF-Y was higher for the g.-1875T allele than for the g.-1875A allele. NF-Y could also repress OCTN1 transcription. These data suggest that three OCTN1 promoter haplotypes could regulate OCTN1 transcription. To our knowledge, this is the first study to identify functional variants of the OCTN1 promoter.

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Section: Introductionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Identification and Functional Characterization of Novel Genetic Variations in theOCTN1Promoter

Park

Choi

2014

Korean J Physiol Pharmacol

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“…Mutations in the gene cluster that contains the OCTN1 and OCTN2 genes have been associated with autoimmune diseases. OCTN1 variant L503F is associated with familial and sporadic inflammatory bowel disease (Lin et al ., 2010). Functionally, this variant has altered substrate specificity with a significantly increased affinity for the common model substrate TEA (Urban et al ., 2007).…”

Section: Octsmentioning

confidence: 99%

OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies

Roth

Obaidat

Hagenbuch

2012

British J Pharmacology

667

661

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The human organic anion and cation transporters are classified within two SLC superfamilies. Superfamily SLCO (formerly SLC21A) consists of organic anion transporting polypeptides (OATPs), while the organic anion transporters (OATs) and the organic cation transporters (OCTs) are classified in the SLC22A superfamily. Individual members of each superfamily are expressed in essentially every epithelium throughout the body, where they play a significant role in drug absorption, distribution and elimination. Substrates of OATPs are mainly large hydrophobic organic anions, while OATs transport smaller and more hydrophilic organic anions and OCTs transport organic cations. In addition to endogenous substrates, such as steroids, hormones and neurotransmitters, numerous drugs and other xenobiotics are transported by these proteins, including statins, antivirals, antibiotics and anticancer drugs. Expression of OATPs, OATs and OCTs can be regulated at the protein or transcriptional level and appears to vary within each family by both protein and tissue type. All three superfamilies consist of 12 transmembrane domain proteins that have intracellular termini. Although no crystal structures have yet been determined, combinations of homology modelling and mutation experiments have been used to explore the mechanism of substrate recognition and transport. Several polymorphisms identified in members of these superfamilies have been shown to affect pharmacokinetics of their drug substrates, confirming the importance of these drug transporters for efficient pharmacological therapy. This review, unlike other reviews that focus on a single transporter family, briefly summarizes the current knowledge of all the functionally characterized human organic anion and cation drug uptake transporters of the SLCO and the SLC22A superfamilies. LINKED ARTICLESBJP recently published a themed section on Transporters. To view the papers in this section visit http://dx

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“…65,66 Polymorphisms in SLC22A5, which encodes OCTN2 the carnitine transporter involved in mitochondrial FAO, are associated with CD risk. 67 Deletion of OCTN2 in mice caused spontaneous colitis. 68 Mice deficient in PGC1α, a master regulator of mitochondrial biogenesis, exhibited exacerbated intestinal inflammation associated with decreased mtDNA levels.…”

Section: Mitochondrial Dysfunction and Inflammatory Bowel Diseasesmentioning

confidence: 99%

Gut bacteria signaling to mitochondria in intestinal inflammation and cancer

2019

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The gastrointestinal microbiome plays a pivotal role in physiological homeostasis of the intestine as well as in the pathophysiology of diseases including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Emerging evidence suggests that gut microbiota signal to the mitochondria of mucosal cells, including epithelial cells and immune cells. Gut microbiota signaling to mitochondria has been shown to alter mitochondrial metabolism, activate immune cells, induce inflammasome signaling, and alter epithelial barrier function. Both dysbiosis of the gut microbiota and mitochondrial dysfunction are associated with chronic intestinal inflammation and CRC. This review discusses mitochondrial metabolism of gut mucosal cells, mitochondrial dysfunction, and known gut microbiota-mediated mitochondrial alterations during IBD and CRC.

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OCTN1 variant L503F is associated with familial and sporadic inflammatory bowel disease

Abstract: The present results replicated the association of the OCTN1 rs1050152 (L503F) variant with CD and IBD overall. A weak gender-specific effect of rs1050152 (L503F) on male UC and female CD was observed.

Cited by 22 publications

References 43 publications

Identification and Functional Characterization of Novel Genetic Variations in theOCTN1Promoter

Identification and Functional Characterization of Novel Genetic Variations in theOCTN1Promoter

OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies

Gut bacteria signaling to mitochondria in intestinal inflammation and cancer

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