Carnitine Transport by Organic Cation Transporters and Systemic Carnitine Deficiency

Lahjouji, Karim; Mitchell, Grant A.; Qureshi, Ijaz A.

doi:10.1006/mgme.2001.3207

Cited by 120 publications

(75 citation statements)

References 53 publications

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“…Moreover, genetic mutations in OCTN2 cause systemic carnitine deficiency, characterized by disease of skeletal muscle, cardiac muscle, and liver but not inflammatory or intestinal disease. 44 Genetic studies to resolve the limits of the association using markers p and q telomeric to OCTN1/2 may help to clarify this issue; however, power of resolution will become a critical issue in attempting to resolve this controversy by genetic studies alone. We have calculated that 3200 individuals with CD would need to be genotyped to prove the independence of OCTN1/2 from IGR2230, which is situated between the 2 genes in haplotype block 7.…”

Section: Discussionmentioning

confidence: 99%

The Contribution of OCTN1/2 Variants Within the IBD5 Locus to Disease Susceptibility and Severity in Crohn’s Disease

et al. 2005

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Background & Aims:Recent data suggest that polymorphisms in the organic cation transporter (OCTN) genes OCTN1 (SLC22A4) and OCTN2 (SLC22A5) represent disease-causing mutations within the IBD5 locus (chromosome 5q31). We investigated associations with disease susceptibility, phenotype, and evidence for epistasis with CARD15 in 679 patients with Crohn's disease (CD) or ulcerative colitis (UC). Methods: A total of 374 patients with CD, 305 patients with UC, and 294 healthy controls (HCs) were studied. Genotyping for single nucleotide polymorphisms IGR2096, IGR2198, and IGR2230, OCTN1 variant (SLC22A4 1672C¡T), and OCTN2 variant (SLC22A5 ؊207G¡C) was performed using the TaqMan system. Results: The IBD5 OCTN1 and OCTN2 polymorphisms were in strong linkage disequilibrium (D=, >0.959). IGR2198 variant allele frequency (49.1% vs 40.8%; P ‫؍‬ .0046) and homozygosity (21% vs 14.8%; P ‫؍‬ .044) were associated with CD versus HCs. Variant allelic frequency of OCTN1 (53.6% vs 43%; P ‫؍‬ .0008) and OCTN2 (56.1% vs 48.4%; P ‫؍‬ .0092) polymorphisms and homozygosity for the OCTN1/2-TC haplotype (28.4% vs 16%; P ‫؍‬ .0042) were associated with CD versus HCs. IGR2198 homozygosity and TC homozygosity were associated with stricturing/penetrating disease at follow-up (P ‫؍‬ .011 and P ‫؍‬ .011, respectively) and disease progression (P ‫؍‬ .038 and P ‫؍‬ .049, respectively) on univariate analysis and with need for surgery on multivariate analysis (P ‫؍‬ .016 and P ‫؍‬ .004, respectively). In the absence of the IBD5 risk haplotype, no association of OCTN1/2 variants with CD was detected. No associations were seen with UC. Conclusions: The IBD5 locus influences susceptibility, progression, and need for surgery in CD. However, the contribution of OCTN1/2 variants is not independent of the IBD5 haplotype; a causative role for these genes remains plausible but is not yet proven. Further genetic, functional, and expression data are now required.

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Section: Discussionmentioning

confidence: 99%

The Contribution of OCTN1/2 Variants Within the IBD5 Locus to Disease Susceptibility and Severity in Crohn’s Disease

et al. 2005

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“…The OCTN family is a family of transporter proteins for organic cations, and may also transport carnitine, an essential cofactor of the metabolism of lipids. [57][58][59][60] Carnitine is involved in the transport of long-chain fatty acids into the mitochondria, where fatty acids will undergo b-oxidation. Hence, carnitine is important in the energy production of the cell.…”

Section: Current Status Of Genetics Research In Ibd S Vermeire and P mentioning

confidence: 99%

Current status of genetics research in inflammatory bowel disease

Vermeire¹,

Rutgeerts²

2005

Genes Immun

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The research on genetic susceptibility of inflammatory bowel diseases (IBD) has been tremendous and over 10 chromosomal regions have been identified by genome-wide scanning. Further fine mapping as well as candidate gene studies have already led to the identification of a number of susceptibility genes including CARD15, DLG5, OCTN1 and 2, NOD1, HLA, and TLR4. The CARD15 gene is undoubtedly replicated most widely and most understood at present. CARD15 is involved in the recognition of bacterial peptidoglycan-derived muramyl dipeptide (MDP) and will stimulate secretion of antimicrobial peptides including alpha-defensins (also called cryptdins) to protect the host from invasion. Genetic research in IBD has advanced our understanding of the clinical heterogeneity of the disease and has started to tackle the complex interactions between genetic risk factors and environmental risk factors in IBD. Genes also interfere with the metabolization of drugs and may influence the clinical response and the drug-related toxicity. Interesting pharmacogenetic data with respect to steroids, azathioprine, and infliximab have been generated in IBD. Overall, it is anticipated that genetic markers in the future will be implemented in an integrated molecular diagnostic and prognostic approach of our patients. Genes and Immunity (2005) 6, 637-645.

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“…Because the fetus cannot adequately supply itself with carnitine, placental transport of this nutrient is of high importance [1]. Low fetal concentrations can lead to carnitine deficiency in infants, symptoms of which include muscle weakness, cardiomyopathy, Reye's syndrome, hypoketotic hypoglycemia, and sudden infant death [2,3].…”

Section: Introductionmentioning

confidence: 99%

Contributions of phosphorylation to regulation of OCTN2 uptake of carnitine are minimal in BeWo cells

Rytting

Audus

2008

Biochemical Pharmacology

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Physiological functions of organic cation transporters (OCTs) in the placenta include transporting essential nutrients from the maternal to fetal circulations. OCTN2 transports carnitine with high affinity, and the transport of several drugs has also been shown to be mediated by this transporter. In this work, the role of phosphorylation and dephosphorylation mechanisms in regulating OCTN2 was investigated by observing the effects of various activators and inhibitors of kinases and phosphatases on the uptake of carnitine in BeWo cells, a human choriocarcinoma trophoblast cell line frequently used as an in vitro model of the rate-limiting barrier for maternal-fetal exchange. Preincubation with genistein resulted in significant increases in both alkaline phosphatase (ALP) activity and carnitine uptake. Levamisole, an ALP inhibitor, caused a more substantial decrease in carnitine uptake than expected from its corresponding decrease in ALP activity. It was determined that levamisole competitively inhibits carnitine uptake, with a K i value of 1.01 ± 0.05 mM, and this effect has a greater role in decreasing carnitine uptake than any indirect effects of ALP inhibition upon OCTN2 function. Progesterone also competitively inhibited carnitine uptake (K i = 48.6 ± 5.0 μM), but had no effect on ALP activity in BeWo cells.

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Carnitine Transport by Organic Cation Transporters and Systemic Carnitine Deficiency

Cited by 120 publications

References 53 publications

The Contribution of OCTN1/2 Variants Within the IBD5 Locus to Disease Susceptibility and Severity in Crohn’s Disease

The Contribution of OCTN1/2 Variants Within the IBD5 Locus to Disease Susceptibility and Severity in Crohn’s Disease

Current status of genetics research in inflammatory bowel disease

Contributions of phosphorylation to regulation of OCTN2 uptake of carnitine are minimal in BeWo cells

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