Mitochondrial long chain fatty acid β-oxidation in man and mouse

Chegary, Malika; Brinke, Heleen te; Ruiter, J. P. N.; Wijburg, Frits A.; Stoll, Maria S.K.; Minkler, Paul E.; Weeghel, Michel van; Schulz, Horst; Hoppel, Charles L.; Wanders, Ronald J. A.; Houten, Sander M.

doi:10.1016/j.bbalip.2009.05.006

Cited by 120 publications

(133 citation statements)

References 42 publications

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“…39). This has been attributed to the capacity of LCAD to substitute for VLCAD in mice but not in humans (11,20). This substrate overlap between VLCAD and LCAD in mice may be compensating for VLCAD deficiency during the first months of life and preventing acute metabolic decompensation, unlike the situation in children with null VLCAD gene mutations.…”

Section: Discussionmentioning

confidence: 97%

Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance

Xiong

James

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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The very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme catalyzes the first step of mitochondrial ␤-oxidation. Patients with VLCAD deficiency present with hypoketotic hypoglycemia and cardiomyopathy, which can be exacerbated by fasting and/or cold stress. Global VLCAD knockout mice recapitulate these phenotypes: mice develop cardiomyopathy, and cold exposure leads to rapid hypothermia and death. However, the contribution of different tissues to development of these phenotypes has not been studied. We generated cardiac-specific VLCAD-deficient (cVLCAD Ϫ/Ϫ ) mice by Cre-mediated ablation of the VLCAD in cardiomyocytes. By 6 mo of age, cVLCAD Ϫ/Ϫ mice demonstrated increased end-diastolic and endsystolic left ventricular dimensions and decreased fractional shortening. Surprisingly, selective VLCAD gene ablation in cardiomyocytes was sufficient to evoke severe cold intolerance in mice who rapidly developed severe hypothermia, bradycardia, and markedly depressed cardiac function in response to fasting and cold exposure (ϩ5°C). We conclude that cardiac-specific VLCAD deficiency is sufficient to induce cold intolerance and cardiomyopathy and is associated with reduced ATP production. These results provide strong evidence that fatty acid oxidation in myocardium is essential for maintaining normal cardiac function under these stress conditions. fatty acid oxidation; mitochondria; cardiac metabolism; cardiomyopathy; mouse; VLCAD; cold intolerance FATTY ACIDS ARE THE PREFERRED substrate for ATP production in the mammalian heart. Very long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the first step of mitochondrial ␤-oxidation, the dehydrogenation of acyl-CoAs with 14 to 20 carbon-chain fatty acids. Mutations in the VLCAD gene are the most common inherited long-chain fatty acid oxidation (FAO) disorder, with an incidence currently estimated to be between 1/42,500 and 1/120,000 (3,7,27, 46). Affected individuals demonstrate a variety of clinical symptoms including nonketotic hypoglycemia, heart and liver lipidosis, encephalopathy, skeletal myopathy, cardiomyopathy, arrhythmias, and sudden death (2,5,7,22,34). Because VLCAD is highly expressed in the liver, heart, lung, brown adipose tissue (BAT), and skeletal muscles, global VLCAD deficiency causes multiple organ dysfunction and diverse clinical symptoms. Three phenotypes have been described: 1) a severe childhood form with no residual enzyme activity, typically presenting with cardiomyopathy and resulting in high mortality (2, 29, 41); 2) a milder childhood form with hypoketotic hypoglycemia as the main feature (2, 3) and 3) an adult presentation with intermittent skeletal myopathy mainly triggered by fasting or exercise (2).Global VLCAD knockout (KO) mice recapitulate some features of human VLCAD deficiency. Adult KO mice demonstrate cardiomyopathy with increased numbers of degenerative fibers, collagen deposition, and vacuolated myocytes as well as increased lipid accumulation in cardiomyocytes (16), abnormal cardiac electrophysiological changes including facilitated i...

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Section: Discussionmentioning

confidence: 97%

Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance

Xiong

James

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…After 96 hours, the medium was removed from the cells, followed by deproteinization using acetonitrile, with subsequent analysis of the acylcarnitines by tandem mass spectrometry. 17,26 These measurements were done in duplicate.…”

Section: Acylcarnitine Profilingmentioning

confidence: 99%

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

Diekman

Ferdinandusse

Pol

et al. 2015

Genetics in Medicine

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Purpose: Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid β-oxidation (LC-FAO) and is included in many newborn screening (NBS) programs worldwide. Patients may present with hypoketotic hypoglycemia, cardiomyopathy, and/or myopathy, but clinical severity varies widely and the clinical outcome is unpredictable. We investigated predictive markers that may determine clinical severity. Methods:We developed a clinical severity score (CSS), which was determined for 13 Dutch patients with VLCADD, all of whom were diagnosed before the introduction of VLCADD in NBS to prevent bias from early diagnosis. In cultured skin fibroblasts from these patients, we measured LC-FAO flux (the rate of oleate oxidation), VLCAD activity, and acylcarnitine profiles following palmitate loading. Results:The strongest correlation (r = 0.93; P < 0.0001) was observed between LC-FAO flux and the CSS. VLCAD activity measurement and the C14/C16-to-acylcarnitine ratio correlated much less. A median LC-FAO flux of 6% of control values (range 5.6-6.8%) was associated with cardiomyopathy (P < 0.01), and 32.4% (range 5.6-50.5%) was associated with myopathy (P < 0.05). Conclusion:Our results demonstrate a very strong correlation between LC-FAO flux in fibroblasts and the clinical severity of VLCADD. LC-FAO flux measurements may thus predict whether patients are likely to develop symptoms.

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“…Additionally, ACAD9 interacts with complex I of the respiratory chain and may have other functions besides its ACAD activity (8,9). In contrast to VLCAD and ACAD9, LCAD expression is low or nearly absent in liver, heart, and muscle and most abundant in lung, kidney, thyroid, and prostate (4,10,11).…”

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confidence: 99%

Long-chain Acyl-CoA Dehydrogenase Deficiency as a Cause of Pulmonary Surfactant Dysfunction

Goetzman

Alcorn

Bharathi

et al. 2014

Journal of Biological Chemistry

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Background:The contribution of long-chain acyl-CoA dehydrogenase (LCAD) to human fatty acid oxidation is not understood. Results: LCAD localizes to lung alveolar type II cells, which produce pulmonary surfactant; LCAD-deficient mice have surfactant dysfunction. Conclusion: LCAD is important for lung energy metabolism and lung function. Significance: LCAD may play a role in human lung disease and unexplained sudden infant death.

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Mitochondrial long chain fatty acid β-oxidation in man and mouse

Cited by 120 publications

References 42 publications

Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance

Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

Long-chain Acyl-CoA Dehydrogenase Deficiency as a Cause of Pulmonary Surfactant Dysfunction

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