Dietary fish oil attenuates cardiac hypertrophy in lipotoxic cardiomyopathy due to systemic carnitine deficiency

Takahashi, Ryōsuke; Okumura, Kenji; Asai, Tomohiro; Hirai, Tatsuya; Murakami, Hisashi; Murakami, Ryuichiro; Numaguchi, Yasushi; Ito, Masafumi; Murohara, Toyoaki

doi:10.1016/j.cardiores.2005.05.018

Cited by 30 publications

(33 citation statements)

References 47 publications

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“…However, in mice subjected to AAC, the myocardial triacylglycerol level was significantly reduced to identical levels in both WT and jvs/ϩ mice, and the 1,2-diacylglycerol level in jvs/ϩ mice was significantly reduced to WT mice levels. In contrast to the dramatic alteration of the fatty acid composition of myocardial 1,2-diacylglycerol in homozygous JVS mice as demonstrated in our previous reports, 9,15,23,32 jvs/ϩ-sham mice did not show significant alteration in the fatty acid composition of 1,2-diacylglycerol. Although mice subjected to AAC showed changes in fatty acid composition of myocardial 1,2-diacylglycerol compared with sham-operated mice, there was no difference between WT-AAC and jvs/ϩ-AAC mice.…”

Section: Discussionmentioning

confidence: 38%

“…9,15,23,32 In the present study, we have also carried out myocardial lipid analysis in heterozygous JVS mice subjected to pressure overload (Table S2). In contrast to homozygous JVS mice, jvs/ϩ-sham mice showed only a modest but significant increase in myocardial triacylglycerol and 1,2-diacylglycerol levels compared with WT-sham mice.…”

Section: Discussionmentioning

confidence: 99%

“…8 Homozygous JVS mice develop cardiomyopathy characterized by marked cardiac hypertrophy without fibrosis, myocardial energy metabolism disorder, 8 and progressive cardiac dysfunction. 9 It was reported that myocardial carnitine levels were also lower in heterozygous mutants of JVS mice compared with WT mice. 10 Although there were no differences in the heart weight:body weight ratio and the mortality rate between WT mice and heterozygous JVS mice, heterozygous mice showed an age-associated increase in left ventricular myocyte diameters compared with WT mice.…”

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Pressure Overload-Induced Cardiomyopathy in Heterozygous Carrier Mice of Carnitine Transporter Gene Mutation

et al. 2007

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Abstract-Primary systemic carnitine deficiency is an autosomal recessive disorder caused by a decreased renal reabsorption of carnitine because of mutations of the carnitine transporter OCTN2 gene, and hypertrophic cardiomyopathy is a common clinical feature of homozygotes. Although heterozygotes for OCTN2 mutations are generally healthy with normal cardiac performance, heterozygotes may be at risk for cardiomyopathy in the presence of additional risk factors, such as hypertension. To test this hypothesis, we investigated the effects of surgically induced pressure overload on the hearts of heterozygous mutants of a murine model of OCTN2 mutation, juvenile visceral steatosis mouse (jvs/ϩ). Eleven-week-old jvs/ϩ mice and age-matched wild-type mice were used. At baseline, there were no differences in physical characteristics between wild-type and jvs/ϩ mice. However, plasma and myocardial total carnitine levels in jvs/ϩ mice were lower than in wild-type mice. Both wild-type and jvs/ϩ mice were subjected to ascending aortic constriction with or without 1% L-carnitine supplementation for 4 weeks. At 4 weeks after ascending aortic constriction, jvs/ϩ mice showed an exaggeration of cardiac hypertrophy and pulmonary congestion, further increased gene expression of atrial natriuretic peptide in the left ventricles, further deterioration of left ventricular fractional shortening, reduced myocardial phosphocreatine:adenosine triphosphate ratio, and increased mortality compared with wild-type mice; L-carnitine supplementation prevented these changes in jvs/ϩ mice subjected to ascending aortic constriction. In conclusion, cardiomyopathy and heart failure with energy depletion may be induced by pressure overload in heterozygotes for OCTN2 mutations and could be prevented by L-carnitine supplementation. Key Words: cardiomyopathy Ⅲ genes Ⅲ heart failure Ⅲ hypertension Ⅲ hypertrophy M itochondrial ␤-oxidation of fatty acids is the main source of energy for the heart. 1 Inborn errors in myocardial fatty acid oxidation have been reported to be important causes of inherited cardiomyopathies, which are typically hypertrophic with diminished systolic function. 2 Carnitine is essential for the transport of long-chain fatty acids into the mitochondrial matrix for ␤-oxidation and plays an important role in cellular energy metabolism. 3 Carnitine deficiency leads to energy an metabolism disorder because of impaired fatty acid oxidation. Primary systemic carnitine deficiency (SCD; Online Mendelian Inheritance in Man 212140) is an autosomal recessive disorder caused by decreased renal reabsorption of carnitine because of mutations of the carnitine transporter OCTN2 gene. 4 Progressive cardiomyopathy is a common clinical manifestation of SCD and could be prevented by high-dose L-carnitine supplementation. 5,6 The juvenile visceral steatosis (JVS) mouse was established as an excellent murine model of SCD. 7 SCD in JVS mice is caused by decreased renal reabsorption of carnitine because of a spontaneous mutation in the OCTN2 gene, as has be...

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Section: Discussionmentioning

confidence: 38%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Pressure Overload-Induced Cardiomyopathy in Heterozygous Carrier Mice of Carnitine Transporter Gene Mutation

et al. 2007

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“…Duda et al (11) reported that, in a rat model of pressure overload, the increase in left ventricular mass was less marked in the FO-fed group compared with rats fed the contrast diet (rich in saturated fat). A FO diet-induced reduction in ventricular mass in a murine model of systemic carnitine deficiency (JVS mice) where cardiac enlargement occurs secondary to lipotoxicity has also been reported (45). The mechanisms leading to regression of cardiac hypertrophy in vivo remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Dietary fish oil is antihypertrophic but does not enhance postischemic myocardial function in female mice

Huggins¹,

Curl²,

Patel³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…The filtrate was centrifuged in a Millipore Microcon centrifugal filter (YM-10, 10 000 MW, Millipore) for 10 min at 12 000 g. The filtrate was assayed for total carnitine (including acylcarnitine and free carnitine) using the enzymatic cycling method (Total carnitine 'Kainos' , Kainos Laboratories, Tokyo, Japan). 22 Light and Electron Microscopy BAT samples for examination by light microscopy were fixed in 10% phosphate-buffered formalin (pH 7.4), processed into wax blocks, sectioned (4 mm thick) and stained with hematoxylin and eosin. Tissue fragments of BAT for electron microscopy were fixed with 2.5% glutaraldehyde in 0.1 M phosphate buffer, pH 7.4.…”

Section: Total Carnitine Assaymentioning

confidence: 99%

Carnitine is necessary to maintain the phenotype and function of brown adipose tissue

Ozaki

Sano

Tsuji

et al. 2011

Laboratory Investigation

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The juvenile visceral steatosis (JVS) mouse is a mutant strain with an inherited systemic carnitine deficiency. Mice of this strain show clinical signs attributable to impaired heat production and disturbed energy production. Brown adipose tissue (BAT) is the primary site of non-shivering thermogenesis in the presence of uncoupling protein-1 (UCP-1) in rodents and humans, especially in infants. To investigate the possible cause of impaired heat production in BAT, we studied the morphological features, carnitine concentration, and UCP-1 production of BAT in JVS mice. The effect of carnitine administration on these parameters was also examined. JVS mice aged 5 or 10 days (60 each) and age-matched control mice were used in this study, along with 10-day-old JVS mice treated subcutaneously with L-carnitine once a day between postpartum days 5 and 10. JVS mice showed lower body temperatures and lower concentrations of carnitine in BAT. Morphologically, BAT cells in JVS mice contained large lipid vacuoles and small mitochondria, similar to those present in white adipose tissue cells. In addition, UCP-1 mRNA and protein expression levels were significantly reduced in JVS as compared with control mice. Carnitine treatment resulted in significant increases in body temperature and carnitine concentrations in BAT, together with the recovery of normal morphological features. UCP-1 mRNA and protein expression levels were also significantly increased. These findings strongly suggest that carnitine is essential for maintaining the function and morphology of BAT.

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Dietary fish oil attenuates cardiac hypertrophy in lipotoxic cardiomyopathy due to systemic carnitine deficiency

Cited by 30 publications

References 47 publications

Pressure Overload-Induced Cardiomyopathy in Heterozygous Carrier Mice of Carnitine Transporter Gene Mutation

Pressure Overload-Induced Cardiomyopathy in Heterozygous Carrier Mice of Carnitine Transporter Gene Mutation

Dietary fish oil is antihypertrophic but does not enhance postischemic myocardial function in female mice

Carnitine is necessary to maintain the phenotype and function of brown adipose tissue

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