Identification of the Up- and Down-Regulated Genes in the Heart of Juvenile Visceral Steatosis Mice

Suenaga, Masaya; Kuwajima, Masamichi; Himeda, Toshiki; Morokami, Kayoko; Matsuura, Tetsuro; Ozaki, Kiyokazu; Arakaki, Naokatu; Shibata, Hirofumi; Higuti, Tomihiko

doi:10.1248/bpb.27.496

Cited by 7 publications

(4 citation statements)

References 37 publications

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“…For example, in humans, defects in the Na ϩ -carnitine cotransporter (Na ϩ -driven organic cation transporter 2 [OCTN2]) cause a cardiomyopathy characterized by cardiac lipid accumulation and hypertrophy (34). Similarly, mice with juvenile visceral steatosis (JVS) mouse mimics human systemic carnitine deficiency because mice with JVS have a spontaneous deficiency of OCTN2 that results in cardiac lipid accumulation and hypertrophy, as well as a 2-fold increase in cardiac mitochondrial area (45). Inhibition of CPT1 and acyl-carnitine synthesis in rats leads to cardiac hypertrophy (39), and mice deficient in long-chain acylCoA dehydrogenase (LCAD) (11) or very-long-chain acylCoA dehydrogenase (VLCAD) (17) also develop cardiac hypertrophy, increased mitochondrial biogenesis, and TAG accumulation.…”

Section: Discussionmentioning

confidence: 99%

Mouse Cardiac Acyl Coenzyme A Synthetase 1 Deficiency Impairs Fatty Acid Oxidation and Induces Cardiac Hypertrophy

Ellis

Mentock

DePetrillo

et al. 2011

Molecular and Cellular Biology

165

221

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Long-chain acyl coenzyme A (acyl-CoA) synthetase isoform 1 (ACSL1) catalyzes the synthesis of acyl-CoA from long-chain fatty acids and contributes the majority of cardiac long-chain acyl-CoA synthetase activity. To understand its functional role in the heart, we studied mice lacking ACSL1 globally (Acsl1 T؊/؊ ) and mice lacking ACSL1 in heart ventricles (Acsl1 H؊/؊ ) at different times. Compared to littermate controls, heart ventricular ACSL activity in Acsl1 T؊/؊ mice was reduced more than 90%, acyl-CoA content was 65% lower, and long-chain acyl-carnitine content was 80 to 90% lower. The rate of [ 14 C]palmitate oxidation in both heart homogenate and mitochondria was 90% lower than in the controls, and the maximal rates of [ 14 C]pyruvate and [ 14 C]glucose oxidation were each 20% higher. The mitochondrial area was 54% greater than in the controls with twice as much mitochondrial DNA, and the mRNA abundance of Pgc1␣ and Err␣ increased by 100% and 41%, respectively. Compared to the controls, Acsl1 T؊/؊ and Acsl1 H؊/؊ hearts were hypertrophied, and the phosphorylation of S6 kinase, a target of mammalian target of rapamycin (mTOR) kinase, increased 5-fold. Our data suggest that ACSL1 is required to synthesize the acyl-CoAs that are oxidized by the heart, and that without ACSL1, diminished fatty acid (FA) oxidation and compensatory catabolism of glucose and amino acids lead to mTOR activation and cardiac hypertrophy without lipid accumulation or immediate cardiac dysfunction.The mitochondrial oxidation of long-chain fatty acids (FAs) provides 60 to 90% of heart ATP (9, 43, 49). Reduced cardiac FA oxidation and increased glucose utilization are a proposed consequence of pathological left ventricular hypertrophy (LVH) (22,33). However, when genes that encode enzymes of FA oxidation are knocked out in mice, LVH develops (11,20). Thus, it remains unclear whether the shift in substrate use is a cause or consequence of cardiac hypertrophy and whether the increased use of glucose interferes with cardiac function.Long-chain acyl coenzyme A (acyl-CoA) synthetase (ACSL) isoenzymes convert FAs to acyl coenzyme A (acyl-CoA) in an ATP-dependent manner, simultaneously activating and trapping FAs within cells (4). Activation to acyl-CoA is required before FAs can be either oxidized to provide ATP or esterified to synthesize triacylglycerol (TAG) or membrane phospholipids (PL). The activation of FA is catalyzed by one of a family of five long-chain acyl-CoA synthetases (ACSLs), long-chain acyl-CoA synthetase isoform 1 (ACSL1), ACSL3, ACSL4, ACSL5, and ACSL6, which differ in substrate preference, enzyme kinetics, subcellular location, and tissue-specific expression (10). Because amphipathic acyl-CoAs can move freely within a membrane monolayer or be transported to distant membranes, all acyl-CoAs should, theoretically, be metabolically equivalent, no matter which ACSL isoenzyme catalyzes their formation and no matter which subcellular organelle is the site of their synthesis. Yet, both loss-of-function and gainof-function studies s...

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Section: Discussionmentioning

confidence: 99%

Mouse Cardiac Acyl Coenzyme A Synthetase 1 Deficiency Impairs Fatty Acid Oxidation and Induces Cardiac Hypertrophy

Ellis

Mentock

DePetrillo

et al. 2011

Molecular and Cellular Biology

165

221

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“…The mice used for this study were JVS mice produced by in vitro fertilization according to the method reported by Suenaga et al [23]. C57BL/6J mice (Clea Japan, Inc., Japan) served as normal controls.…”

Section: Experimental Animalsmentioning

confidence: 99%

Reduced Carnitine Level Causes Death from Hypoglycemia: Possible Involvement of Suppression of Hypothalamic Orexin Expression During Weaning Period

et al. 2007

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Abstract. The mechanism of onset of hypoglycemia in patients with carnitine deficiency has yet to be determined. Using mice with systemic carnitine deficiency (JVS mice), we examined this mechanism, focusing on the weaning period (days 14-28 postpartum). For normal mice, the survival rate was 100%, and no hypoglycemia was observed at all. Gastric lactose began to decrease on day 17, and cellulose increased sharply in amount thereafter. For JVS mice, the survival rate was 77% on day 14 and 28% on day 28. From day 21 on, hypoglycemia was noted. Gastric lactose had disappeared almost completely by day 17, and cellulose was almost undetectable from days 14 to 28. Expression of orexin mRNA in the hypothalamus did not differ between JVS and normal mice on day 14, but was suppressed in JVS mice on days 21 and 28. When JVS mice were fed a carnitine-rich diet, suppression of expression of orexin mRNA in hypothalamus was eliminated, and on day 28 lactose and cellulose were detected in the stomach without hypoglycemia. In conclusion, the suppression of the expression of orexin in the hypothalamus during the weaning period may be involved in the marked anorexia in JVS mice, which eventually leads to death from hypoglycemia.

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“…Studies in the CUD mouse model suggest that tissue levels of carnitine are resistant to the effect of low plasma carnitine levels, 26 and there is a compensatory increase in the expression of other genes involved in fatty acid oxidation and mitochondrial metabolism. 27 In the CUD animal model, the compensatory increased expression of the carnitine palmitoyltransferase 1 gene is repressed with oral carnitine. 28 The NZ treatment experience is that there are difficulties with compliance in our adult CUD patients.…”

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confidence: 99%

The decision to discontinue screening for carnitine uptake disorder in New Zealand

Wilson

Knoll

Hora

et al. 2019

J of Inher Metab Disea

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When screening for carnitine uptake disorder (CUD), the New Zealand (NZ) newborn screening (NBS) service identified infants as screen-positive if they had initial and repeat free carnitine (C0) levels of less than 5.0 μmol/L. Since 2006, the NBS service has identified two infants with biochemical and genetic features consistent with neonatal CUD and nine mothers with features consistent with maternal CUD. A review of the literature suggests that these nine women reflect less than half the true prevalence and that CUD is relatively common. However, the NZ results (two infants) suggest a very low sensitivity and positive predictive value of NBS.While patients presenting with significant disease due to CUD are well described, the majority of adults with CUD are asymptomatic. Nonetheless, treatment with highdose oral L-carnitine is recommended. Compliance with oral L-carnitine is likely to be poor long term. This may represent a specific risk as treatment could repress the usual compensatory mechanisms seen in CUD, such that a sudden discontinuation of treatment may be dangerous. L-carnitine is metabolized to trimethylamine-N-oxide (TMAO) and treated patients have extremely high plasma TMAO levels. TMAO is an independent risk factor for atherosclerosis and, thus, caution should be exercised regarding long-term treatment with high-dose carnitine of asymptomatic patients who may have a biochemical profile without disease. Due to these concerns, the NZ Newborn Metabolic Screening Programme (NMSP) initiated a review via a series of advisory and governance committees and decided to discontinue screening for CUD.

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Identification of the Up- and Down-Regulated Genes in the Heart of Juvenile Visceral Steatosis Mice

Cited by 7 publications

References 37 publications

Mouse Cardiac Acyl Coenzyme A Synthetase 1 Deficiency Impairs Fatty Acid Oxidation and Induces Cardiac Hypertrophy

Mouse Cardiac Acyl Coenzyme A Synthetase 1 Deficiency Impairs Fatty Acid Oxidation and Induces Cardiac Hypertrophy

Reduced Carnitine Level Causes Death from Hypoglycemia: Possible Involvement of Suppression of Hypothalamic Orexin Expression During Weaning Period

The decision to discontinue screening for carnitine uptake disorder in New Zealand

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