Very-Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency in Mice

Exil, Vernat; Roberts, Richard L.; Sims, Harold F.; McLaughlin, Jacquelin E.; Malkin, R.A.; Gardner, Carla D.; Ni, Gemin; Rottman, Jeffrey N.; Strauss, Arnold W.

doi:10.1161/01.res.0000088786.19197.e4

Cited by 114 publications

(110 citation statements)

References 26 publications

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“…In this model, ACSL1 overexpression probably activated large amounts of acyl-CoA within cardiomyocytes, without a concomitant increase in oxidative demand. Thus, similarly to VLCAD and LCAD null mice, in which mitochondrial FA oxidation is partially blocked (11,17), excess and potentially toxic acyl-CoAs are esterified to form triacylglycerol (TAG). In contrast to these models, lack of ACSL1 prevents FA activation, thereby both blocking FA metabolism and preventing FAs from being trapped as acyl-CoA within cells.…”

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

164

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

164

221

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“…VLCAD Ϫ/Ϫ mice were generated as described (6,12). Genotypes were determined by duplicate PCR analyses (13).…”

Section: Methodsmentioning

confidence: 99%

Carnitine Supplementation Induces Acylcarnitine Production in Tissues of Very Long-Chain Acyl-CoA Dehydrogenase-Deficient Mice, Without Replenishing Low Free Carnitine

et al. 2008

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Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD) results in accumulation of C14 -C18 acylcarnitines and low free carnitine. Carnitine supplementation is still controversial. VLCAD knockout (VLCAD Ϫ/Ϫ ) mice exhibit a similar clinical and biochemical phenotype to those observed in humans. VLCAD Ϫ/Ϫ mice were fed with carnitine dissolved in drinking water. Carnitine, acylcarnitines, and ␥-butyrobetaine were measured in blood and tissues. Measurements were performed under resting conditions, after exercise and after 24 h of regeneration. HepG2 cells were incubated with palmitoyl-CoA and palmitoyl-carnitine, respectively, to examine toxicity. With carnitine supplementation, acylcarnitine production was significantly induced. Nevertheless, carnitine was low in skeletal muscle after exercise. Without carnitine supplementation, liver carnitine significantly increased after exercise, and after 24 h of regeneration, carnitine concentrations in skeletal muscle completely replenished to initial values. Incubation of hepatic cells with palmitoylCoA and palmitoyl-carnitine revealed a significantly reduced cell viability after incubation with palmitoyl-carnitine. The present study demonstrates that carnitine supplementation results in significant accumulation of potentially toxic acylcarnitines in tissues. The expected prevention of low tissue carnitine was not confirmed. The principle mechanism regulating carnitine homeostasis seems to be endogenous carnitine biosynthesis, also under conditions with increased demand of carnitine such as in VLCAD-deficiency. V ery long-chain acyl-CoA dehydrogenase (VLCAD or ACADVL, EC 1.3.99.3) is one of several enzymes of mitochondrial ␤-oxidation. Deficiency of VLCAD is the most common mitochondrial ␤-oxidation defect of long-chain fatty acids, with an occurrence of approximately 1:50.000 to 1:100.000 births (1). In humans, VLCAD-deficiency (VLCADD) is characterized by phenotypic heterogeneity. Phenotypic presentation is heterogeneous and different forms of presentation are distinguished: a severe early onset form presenting with cardiomyopathy and Reye-like symptoms; a hepatic phenotype that usually expresses in infancy with recurrent hypoketotic hypoglycemia; and a milder, later-onset, myopathic form with episodic muscle weakness and rhabdomyolysis (2). However, the hepatic phenotype of infancy will often become a muscular phenotype during childhood and adolescence. Exercise or catabolic stress such as illnesses trigger clinical symptoms. With the start of neonatal screening programs for fatty acid oxidation defects the majority of patients are asymptomatic at time of diagnosis and remain asymptomatic with preventive measures during the first years of follow-up. Especially for this group of patients, there is a need to define risk factors for the manifestation of clinical symptoms with special respect to physical exercise. Deficient oxidation of long-chain acyl-CoAs, especially during catabolism, results in accumulation of long-chain acylcarnitines.Carnitine is an es...

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“…Echocardiography and blood pressure measurement. At 16 weeks of age, transthoracic echocardiograms were performed on resting conscious mice using a 15-MHz transducer (Sonos 5500 system; Agilent) as previously described (7,8). In addition, systolic blood pressure was measured in conscious mice using tail-cuff plethysmography (9).…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation Barriers to Skeletal and Cardiac Muscle Glucose Uptakes in High-Fat–Fed Mice

et al. 2007

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OBJECTIVE-Muscle glucose uptake (MGU) is regulated by glucose delivery to, transport into, and phosphorylation within muscle. The aim of this study was to determine the role of limitations in glucose phosphorylation in the control of MGU during either physiological insulin stimulation (4 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or exercise with chow or high-fat feeding. RESEARCH DESIGN AND METHODS-C57BL/6J mice with (HKϩ/Ϫ ) and without (WT) a 50% hexokinase (HK) II deletion were fed chow or high-fat diets and studied at 4 months of age during a 120-min insulin clamp or 30 min of treadmill exercise (n ϭ 8 -10 mice/group). 2-deoxy[ 3 H]glucose was used to measure R g , an index of MGU.RESULTS-Body weight and fasting arterial glucose were increased by high-fat feeding and partial HK II knockout (HK ϩ/Ϫ ). Both high-fat feeding and partial HK II knockout independently created fasting hyperinsulinemia, a response that was increased synergistically with combined high-fat feeding and HK II knockout. Whole-body insulin action was suppressed by ϳ25% with either high-fat feeding or partial HK II knockout alone but by Ͼ50% when the two were combined. Insulin-stimulated R g was modestly impaired by high-fat feeding and partial HK II knockout independently (ϳ15-20%) but markedly reduced by the two together (ϳ40 -50%). Exercise-stimulated R g was reduced by ϳ50% with high-fat feeding and partial HK II knockout alone and was not attenuated further by combining the two.CONCLUSIONS-In summary, impairments in whole-body metabolism and MGU due to high-fat feeding and partial HK II knockout combined during insulin stimulation are additive. In contrast, combining high-fat feeding and partial HK II knockout during exercise causes no greater impairment in MGU than the two manipulations independently. This suggests that MGU is impaired during exercise by high-fat feeding due to, in large part, a limitation in glucose phosphorylation. Together, these studies show that the high-fat-fed mouse is characterized by defects at multiple steps of the MGU system that are precipitated by different physiological conditions. Diabetes 56:2476-2484, 2007 T he importance of limitations in muscle glucose phosphorylation capacity in insulin resistance is a point of contention. In rodent muscle, glucose phosphorylation to glucose-6-phosphate is catalyzed primarily by the hexokinase (HK) II isozyme. HK II content may be normal (1) or reduced (2) in insulinresistant states, depending on the muscle fiber type composition. Regardless, glucose phosphorylation capacity is affected due to allosteric inhibition of HK II by acyl-CoA and glucose-6-phosphate or compartmentation of HK II, its allosteric regulators, and its substrates (i.e., glucose and ATP). Insulin stimulation and exercise can be used to expose functional deficits in glucose phosphorylation capacity that may otherwise be undetectable (3). Indeed, we previously used such a strategy in conscious mice overexpressing HK II to provide evidence that glucose phosphorylation is, in fact, impaired by high-fat feeding (4). Th...

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Very-Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency in Mice

Cited by 114 publications

References 26 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

Carnitine Supplementation Induces Acylcarnitine Production in Tissues of Very Long-Chain Acyl-CoA Dehydrogenase-Deficient Mice, Without Replenishing Low Free Carnitine

Phosphorylation Barriers to Skeletal and Cardiac Muscle Glucose Uptakes in High-Fat–Fed Mice

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