Proto‐oncogene c‐<i>jun</i> and c‐<i>fos</i> messenger RNAs increase in the liver of carnitine‐deficient juvenile visceral steatosis (jvs) mice

Tomomura, Mineko; Nakagawa, Kyoko; Saheki, Takeyori

doi:10.1016/0014-5793(92)81368-v

Cited by 12 publications

(7 citation statements)

References 26 publications

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“…How carnitine deficiency causes these various abnormalities in the heart and liver is a matter of great interest. Recently, Tomomura et al [21] reported that the expression of the proto-oncogenes, c-jun and c-fos, is increased in the liver of homozygous mutants 0vs/jvs). The relationship between carnitine deficiency and the induction of the proto-oncogenes has not yet been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Cardiac hypertrophy in juvenile visceral steatosis (jvs) mice with systemic carnitine deficiency

et al. 1993

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We have reported the clinical and biochemical findings in juvenile visceral steatosis (jvs) mice with systemic carnitine deficiency. This paper is the first report about cardiomyopathy injvs mice. Adult jvs mice (at the age of 2 3 months) show cardiac hypertrophy which is caused by enlargement of the cardiac muscle cell associated with increases of non-collagen protein and DNA content. Carnitine administration (2 mg/head, twice a day, from 1 month of age) significantly suppresses the cardiac hypertrophy, showing that carnitine deficiency plays an important role in the development of the cardiac hypertrophy. The discovery of cardiac hypertrophy in carnitine-deficient jvs mice will lead to clarification of the pathophysiology of cardiomyopathy in systemic carnitine deficiency in human beings.Cardiac hypertrophy; Systemic carnitine deficiency; Animal model; Juvenile visceral steatosis mice

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Section: Discussionmentioning

confidence: 99%

Cardiac hypertrophy in juvenile visceral steatosis (jvs) mice with systemic carnitine deficiency

et al. 1993

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“…Finally, we assayed the AP-1 DNA binding activity by gel shift analysis of the nuclear fractions from the cultured hepatocytes under the conditions described in Fig. 3, since AP-1 DNA binding was highly activated in the liver of JVS mice [7]. AP-I DNA binding activity observed under basal conditions was reduced by the addition of dexamethasone (Dex).…”

Section: Gel Mobility-shift Assaymentioning

confidence: 99%

“…In hereditary carnitine-deficient JVS mice, the major symptoms in the infantile period are fatty liver, hypoglycaemia and hyperammonemia [1,2]. We have shown that the hyperammonemia is caused by the suppression of urea cycle enzyme genes [3][4][5], which is effectively treated by the administration of carnitine [6] and may be related to enhanced c-jun and c-fos expression and AP-1 DNA binding activity [5,7]. The concentration of free fatty acid in serum is very high in infant JVS mice and in starved adult JVS mice where the induction of the urea cycle enzyme genes is suppressed [8].…”

Section: Introductionmentioning

confidence: 99%

Long‐chain fatty acids suppress the induction of urea cycle enzyme genes by glucocorticoid action

Tomomura¹,

Tomomura²,

Musa³

et al. 1996

FEBS Letters

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In order to test the possibility that free fatty acids are the mediator of the abnormal expression of urea cycle enzyme genes in carnitine-deficient juvenile visceral steatosis (JVS) mice, the effects of fatty acids on urea cycle enzyme, carbamoylphosphate synthetase (CPS) and argininosuccinate synthetase (ASS), mRNA levels were examined in rat primary cultured hepatocytes. Addition of a synthetic glucocorticoid hormone, dexamethasone, caused increases in CPS and ASS mRNAs. Further addition of oleic acid suppressed the induction of CPS and ASS mRNAs by dexamethasone. In contrast, the phosphoenolpyruvate carhoxykinase (PEPCK) mRNA level induced by dexamethasone was enhanced in the presence of oleic acid. The effects were reversed on further addition of carnitine. The mRNA levels of these enzymes induced by dibutyryl cAMP were not affected by the addition of oleic acid. A study of the specificity of fatty acids revealed that long-chain fatty acids of more than 16 carbons chain length had a suppressive effect on the CPS mRNA level induced by dexamethasone and that the presence of double bonds enhanced the effect. The changes in gene expression of CPS, ASS and PEPCK caused by the fatty acids in the cultured hepatocytes were very similar to those observed in the liver of JVS mice. The AP-1 DNA binding activity in the presence of dexamethasone was slightly enhanced by the addition of oleic acid. These results suggest that the long-chain fatty acids not metabolized in JVS mice are mediators of the abnormal gene expression in the liver which results in hyperammonemia.

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“…Abnormalities in the expression of urea cycle enzymes abundant in the liver have been demonstrated [5,13]. Tomomura et al [14] have recently reported an increase in the levels of messenger RNAs encoding the proto-oncogenes c-jun and c-fos, ~x-fetoprotein and aldolase A, suggesting that the hepatocytes of JVS mice are in an undifferentiated or de-differentiated state.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial abnormalities of muscle tissue in mice with juvenile visceral steatosis associated with systemic carnitine deficiency

Miyagawa

Kuwajima

Hanafusa

et al. 1995

Vichows Archiv A Pathol Anat

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A mouse with juvenile visceral steatosis (the JVS mouse) has been recognized as a novel animal model for systemic carnitine deficiency. We examined cardiac, skeletal and smooth muscle cells in JVS and control mice by light and electron microscopy. Cardiac and skeletal muscle cells of these mice at 4 weeks of age exhibited a ragged-red appearance after trichrome staining. Electron microscopy, demonstrated increased numbers of mitochondria and lipid droplets in the cells. Compression or distortion of the myofibril bundles, primarily due to the increased number of mitochondria, suggests the possible existence of a functional disturbance of the cardiac and skeletal muscle. In the urinary bladder, only one or two large lipid droplets and slightly increased number of mitochondria were recognized in the perinuclear region of the smooth muscle cells. At 8 weeks of age, the mouse enzyme histochemistry specific for mitochondria, such as cytochrome c oxidase and succinic dehydrogenase, and oil red O staining, confirmed further increases in the number of mitochondria and lipid droplets in the heart. However, the accumulation of these organelles in the skeletal and smooth muscle cells was no greater than that noted in JVS mice at 4 weeks of age. In the cardiac muscle cells, autolysosomes or autophagic vacuoles containing electron-dense membranous, lamellar or whorled structures closely associated with mitochondria and pseudoinclusion bodies in the nucleus were recognized, and bundles of myofibrils were buried under numerous mitochondria, suggesting the existence of disturbed contractile function in the heart of JVS mice. These results indicate that this murine strain associated with systemic carnitine deficiency exhibits a generalized mitochondrial abnormality in the muscle system especially in the heart.

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Proto‐oncogene c‐jun and c‐fos messenger RNAs increase in the liver of carnitine‐deficient juvenile visceral steatosis (jvs) mice

Cited by 12 publications

References 26 publications

Cardiac hypertrophy in juvenile visceral steatosis (jvs) mice with systemic carnitine deficiency

Cardiac hypertrophy in juvenile visceral steatosis (jvs) mice with systemic carnitine deficiency

Long‐chain fatty acids suppress the induction of urea cycle enzyme genes by glucocorticoid action

Mitochondrial abnormalities of muscle tissue in mice with juvenile visceral steatosis associated with systemic carnitine deficiency

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