Role of mitochondrial acyl-CoA dehydrogenases in the metabolism of dicarboxylic fatty acids
Role of mitochondrial acyl-CoA dehydrogenases in the metabolism of dicarboxylic fatty acids
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DOI：
10.1016/j.bbrc.2020.04.105
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发表时间：
2020-06-18
影响因子：
3.1
通讯作者：
Goetzman, Eric S.
中科院分区：
文献类型：
--
作者：
Bharathi, Sivakama S.;Zhang, Yuxun;Goetzman, Eric S.
二羧酸脂肪酸，作为一种营养补充剂或通过一元羧酸脂肪酸的ω氧化内源性产生，可能对罕见的先天性代谢缺陷以及常见的代谢疾病如2型糖尿病具有治疗潜力。二羧酸的分解产生乙酰辅酶A和琥珀酰辅酶A作为产物，后者对于TCA循环是回补的。然而，对二羧酸降解的代谢途径知之甚少。在这里，我们证明了与全细胞脂肪酸氧化测定，线粒体和过氧化物酶体有助于二羧酸降解。测试了几种线粒体酰基-CoA脱氢酶对二羧基-CoA的活性。中链酰基辅酶A脱氢酶（MCAD）表现出与6和12碳二羧基辅酶A的活性，这些底物的脱氢能力显着降低在MCAD敲除小鼠肝脏。然而，当二羧酸喂养正常小鼠时，MCAD的表达没有变化，而过氧化物酶体脂肪酸氧化酶的表达大大上调。总之，线粒体脂肪酸氧化，特别是MCAD，有助于二羧酸降解，但喂食二羧酸仅诱导过氧化物酶体途径。(c)2020爱思唯尔公司All rights reserved.
Dicarboxylic fatty acids, taken as a nutritional supplement or produced endogenously via omega oxidation of monocarboxylic fatty acids, may have therapeutic potential for rare inborn errors of metabolism as well as common metabolic diseases such as type 2 diabetes. Breakdown of dicarboxylic acids yields acetyl-CoA and succinyl-CoA as products, the latter of which is anaplerotic for the TCA cycle. However, little is known about the metabolic pathways responsible for degradation of dicarboxylic acids. Here, we demonstrated with whole-cell fatty acid oxidation assays that both mitochondria and peroxisomes contribute to dicarboxylic acid degradation. Several mitochondrial acyl-CoA dehydrogenases were tested for activity against dicarboxylyl-CoAs. Medium-chain acyl-CoA dehydrogenase (MCAD) exhibited activity with both six and 12 carbon dicarboxylyl-CoAs, and the capacity for dehydrogenation of these substrates was significantly reduced in MCAD knockout mouse liver. However, when dicarboxylic acids were fed to normal mice, the expression of MCAD did not change, while expression of peroxisomal fatty acid oxidation enzymes was greatly upregulated. In conclusion, mitochondrial fatty acid oxidation, and in particular MCAD, contributes to dicarboxylic acid degradation, but feeding dicarboxylic acids induces only the peroxisomal pathway. (c) 2020 Elsevier Inc. All rights reserved.