Antagonizing Effect of AP-1 on Glucocorticoid Induction of Urea Cycle Enzymes: A Study of Hyperammonemia in Carnitine-Deficient, Juvenile Visceral Steatosis Mice

Saheki, Takeyori; Li, Meng Xian; Kobayashi, Keiko

doi:10.1006/mgme.2000.3093

Cited by 13 publications

(8 citation statements)

References 29 publications

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“…Activities of all urea cycle enzymes were suppressed in these animals, for example, the mean carbamoyl phosphate synthetase (CPS) activity was only 11% of normal (Imamura et al, 1990). Subsequent studies from the same group reported that oleic acid suppressed expression of CPS gene through a direct interaction on an AP-1 element which acted as an enhancer of CPS gene (Saheki et al, 2000). Therefore, secondary hyperammonaemia in human may be caused by a similar mechanism.…”

Section: Discussionmentioning

confidence: 99%

A founder mutation (R254X) of SLC22A5 (OCTN2) in Chinese primary carnitine deficiency patients

et al. 2002

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Mutations in the SLC22A5 gene, which encodes for the plasma membrane carnitine transporter OCTN2, cause primary carnitine deficiency (PCD). After our first report of OCTN2 mutations in Chinese, three more Chinese PCD patients were identified. The parents of these families were non-consanguineous and these families were unrelated. Two novel truncating mutations were found: R254X, a single-base mutation at cDNA position 981 (c.981C>T); and Y387X (c.1382T>G). Two probands, one each from Taiwan and Macau, were homozygous for R254X. The other proband from Taiwan carried both R254X and Y387X. Two additional heterozygote carriers of R254X were also identified among 250 control samples, while none was detected for Y387X. The population carrier rate for R254X would be about 1 in 125. Haplotypes of R254X alleles were examined and patients homozygous for R254X were also homozygous for the same haplotype of intragenic and microsatellites markers. Analysis of population frequencies of haplotypes revealed that the chance of 4 chromosomes having arisen as independent events was 0.016. We conclude that R254X is probably a founder mutation in Chinese. Other previously reported mutations found in the Japanese population were also screening in 250 control samples but no carrier was identified, indicating that they were either very rare or not present in Southern Chinese.

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Section: Discussionmentioning

confidence: 99%

A founder mutation (R254X) of SLC22A5 (OCTN2) in Chinese primary carnitine deficiency patients

et al. 2002

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“…(Maebashi et al 1982;Gadaleta et al 1990). In addition, it has recently been shown (Saheki et al 2000) that l-carnitine has the potential to downregulate Fos/Jun, of which high levels are known to inhibit the GRE (glucocorticoid-responsive element) and TRE (e.g., Jonat et al 1990;Bodenner et al 1992). Thus, l-carnitine has the potential to upregulate genes such as CPT1A and carbamoylphosphate synthetase which have TRE and GRE in their promoter regions (eg.…”

Section: Discussionmentioning

confidence: 99%

Dietary L-carnitine Stimulates Carnitine Acyltransferases in the Liver of Aged Rats

Karlic

Lohninger

Koeck

et al. 2002

J Histochem Cytochem.

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S U M M A R YAging affects oxidative metabolism in liver and other tissues. Carnitine acyltransferases are key enzymes of this process in mitochondria. As previously shown, the rate of transcription and activity of carnitine palmitoyltransferase CPT1 are also related to carnitine levels. In this study we compared the effect of dietary L -carnitine (100 mg L -carnitine/ kg body weight/day over 3 months) on liver enzymes of aged rats (months 21-24) to adult animals (months 6-9) and age-related controls for both groups. The transcription rate of CPT1, CPT2, and carnitine acetyltransferase (CRAT) was determined by quantitative reverse transcription real-time PCR (RTQPCR) and compared to the activity of the CPT1A enzyme. The results showed that the transcription rates of CPT1, CPT2, and CRAT were similar in aged and adult control animals. Carnitine-fed old rats had a significant ( p Ͻ 0.05) 8-12-fold higher mean transcription rate of CPT1 and CRAT compared to aged controls, adult carnitine-fed animals, and adult controls, whereas the transcription rate of CPT2 was stimulated 2-3-fold in carnitine-fed animals of both age groups. With regard to the enzymatic activity of CPT1 there was a 1.5-fold increase in the old carnitine group compared to all other groups. RNA in situ hybridization also indicated an enhanced expression of CPT1A in hepatocytes from L -carnitine-supplemented animals. These results suggest that L -carnitine stimulates transcription of CPT1, CPT2, and CRAT as well as the enzyme activity of CPT1 in the livers of aged rats.

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“…Laboratory evaluation usually reveals hypoglycemia, with minimal or no ketones in urine, and hyperammonemia, with variably elevated liver function tests. Hyperammonemia is likely caused by decreased expression of urea cycle enzymes in the liver and is usually observed only during acute decompensation [105]. Creatine kinase can also be mildly elevated [13].…”

Section: Disorders Of Fatty Acid Oxidationmentioning

confidence: 99%

Carnitine transport and fatty acid oxidation

Longo

Frigeni

Pasquali

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

666

506

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Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. It can be synthesized by the body or assumed with the diet from meat and dairy products. Defects in carnitine biosynthesis do not routinely result in low plasma carnitine levels. Carnitine is accumulated by the cells and retained by kidneys using OCTN2, a high affinity organic cation transporter specific for carnitine. Defects in the OCTN2 carnitine transporter results in autosomal recessive primary carnitine deficiency characterized by decreased intracellular carnitine accumulation, increased losses of carnitine in the urine, and low serum carnitine levels. Patients can present early in life with hypoketotic hypoglycemia and hepatic encephalopathy, or later in life with skeletal and cardiac myopathy or sudden death from cardiac arrhythmia, usually triggered by fasting or catabolic state. This disease responds to oral carnitine that, in pharmacological doses, enters cells using the amino acid transporter B0,+. Primary carnitine deficiency can be suspected from the clinical presentation or identified by low levels of free carnitine (C0) in the newborn screening. Some adult patients have been diagnosed following the birth of an unaffected child with very low carnitine levels in the newborn screening. The diagnosis is confirmed by measuring low carnitine uptake in the patients’ fibroblasts or by DNA sequencing of the SLC22A5 gene encoding the OCTN2 carnitine transporter. Some mutations are specific for certain ethnic backgrounds, but the majority are private and identified only in individual families. Although the genotype usually does not correlate with metabolic or cardiac involvement in primary carnitine deficiency, patients presenting as adults tend to have at least one missense mutation retaining residual activity.

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Antagonizing Effect of AP-1 on Glucocorticoid Induction of Urea Cycle Enzymes: A Study of Hyperammonemia in Carnitine-Deficient, Juvenile Visceral Steatosis Mice

Cited by 13 publications

References 29 publications

A founder mutation (R254X) of SLC22A5 (OCTN2) in Chinese primary carnitine deficiency patients

A founder mutation (R254X) of SLC22A5 (OCTN2) in Chinese primary carnitine deficiency patients

Dietary L-carnitine Stimulates Carnitine Acyltransferases in the Liver of Aged Rats

Carnitine transport and fatty acid oxidation

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