Elsevier

Biochemical Pharmacology

Volume 55, Issue 10, 15 May 1998, Pages 1729-1732
Biochemical Pharmacology

Short Communication
Gene-Dose Effect on Carnitine Transport Activity in Embryonic Fibroblasts of JVS Mice as a Model of Human Carnitine Transporter Deficiency

https://doi.org/10.1016/S0006-2952(97)00670-9Get rights and content

Abstract

Recently, the marked decline in renal carnitine reabsorption has been thought to account for the systemic carnitine deficiency in juvenile visceral steatosis (JVS) mice. We have conducted a kinetic analysis using embryonic fibroblasts derived from normal, heterozygous, and homozygous jvs mice and found that the high-affinity carnitine transporter (Km = 5.5 μM), which shows Na+ and temperature dependency and stereospecificity, is defective in homozygous jvs mice. Moreover, a gene dose-dependent decrease of carnitine transport activity, which was due to a decrease in the number of the transporter molecules, was found in heterozygous jvs mice. Similar phenomena have been observed in human primary carnitine deficiency. Therefore, JVS mice may be useful for understanding this extremely rare human hereditary disorder.

Section snippets

Animals

JVS mice were originally found among mice of the C3H.OH strain in our laboratory (Institute for Experimental Animals, Faculty of Medicine, Kanazawa University). The autosomal recessive mutant gene jvs was then back-crossed into C57BL/6J mice (Clea Japan), and this congenic strain was called “B6-jvs.” Animals were maintained under semi-barrier conditions at 24.0 ± 2.0° with a 12:12 hr light–dark cycle in compliance with the standards set forth in the “Guidelines for the Care and Use of

Carnitine Specific Transporter

Uptake of l-carnitine in immortalized normal mouse embryonic fibroblasts was temperature-dependent and linear for up to 4 hr and had a saturable, substrate concentration-dependent component at 37° (data not shown). This saturable uptake of l-carnitine showed both Na+-dependence (Fig. 1) and stereospecificity (Fig. 2). These observations indicate that l-carnitine uptake occurs via a carnitine-specific transporter-mediated process in normal mouse embryonic fibroblasts.

Kinetic Analysis of Concentration-Dependent Carnitine Transport

Carnitine uptake by

Discussion

Recently, a prenatal diagnosis of human carnitine transporter defect was attempted in a fetus at high risk of having this disorder [13]. In this and some other case studies of primary carnitine-deficiency patients, the defect of carnitine transport activities showed autosomal recessive inheritance (i.e. the parents or nonaffected brother of affected patients showed transport activities intermediate between patients and control) 14, 15.

The JVS mouse was found as a mutant mouse with a hereditary

Acknowledgements

This work was supported, in part, by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan (No. 08458274) and the Ono Pharmaceutical Co., Ltd.

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