Pender Celia, Trentadue Anna R, Pories Walter J, Dohm G Lynis, Houmard Joseph A, Youngren Jack F
Department of Medicine, Diabetes and Endocrine Research, Mount Zion Medical Center, University of California, San Francisco, California 94143-1616, USA.
J Cell Biochem. 2006 Oct 15;99(3):860-7. doi: 10.1002/jcb.20944.
In humans and animal models, increased intramuscular lipid (IML) stores have been implicated in insulin resistance. Malonyl-CoA plays a critical role in cellular lipid metabolism both by serving as a precursor in the synthesis of lipids and by inhibiting lipid oxidation. In muscle, Malonyl-CoA acts primarily as a negative allosteric regulator of carnitine palmitoyl transferase-1 (CPT1) activity, thereby blocking the transport of long chain fatty acyl CoAs into the mitochondria for oxidation. In muscle, increased malonyl-CoA, decreased muscle CPT1 activity, and increased IML have all been reported in obesity. In order to determine whether malonyl-CoA synthesis might be under transcriptional as well as biochemical regulation, we measured mRNA content of several key genes that contribute to the cellular metabolism of malonyl-CoA in muscle biopsies from lean to morbidly obese subjects. Employing quantitative real-time PCR, we determined that expression of mitochondrial acetyl-CoA carboxylase 2 (ACC2) was increased by 50% with obesity (P < 0.05). In both lean and obese subjects, expression of mitochondrial ACC2 was 20-fold greater than that of cytoplasmic ACC1, consistent with their hypothesized roles in synthesizing malonyl-CoA from acetyl-CoA for CPT1 regulation and lipogenesis, respectively. In addition, in both lean and obese subjects, expression of malonyl-CoA decarboxylase was approximately 40-fold greater than fatty acid synthase, consistent with degradation, rather than lipogenesis, being the primary fate of malonyl-CoA in human muscle. No other genes showed signs of increased mRNA content with obesity, suggesting that there may be selective transcriptional regulation of malonyl-CoA metabolism in human obesity.
在人类和动物模型中，肌肉内脂质（IML）储存增加与胰岛素抵抗有关。丙二酰辅酶A在细胞脂质代谢中起着关键作用，它既是脂质合成的前体，又能抑制脂质氧化。在肌肉中，丙二酰辅酶A主要作为肉碱棕榈酰转移酶-1（CPT1）活性的负变构调节剂，从而阻止长链脂肪酰辅酶A进入线粒体进行氧化。在肥胖人群的肌肉中，已报道丙二酰辅酶A增加、肌肉CPT1活性降低以及IML增加。为了确定丙二酰辅酶A的合成是否受转录调控以及生化调控，我们测量了从瘦人到病态肥胖受试者的肌肉活检样本中，几个参与丙二酰辅酶A细胞代谢的关键基因的mRNA含量。通过定量实时PCR，我们发现肥胖时线粒体乙酰辅酶A羧化酶2（ACC2）的表达增加了50%（P<0.05）。在瘦人和肥胖受试者中，线粒体ACC2的表达均比细胞质ACC1高20倍，这与其分别在从乙酰辅酶A合成丙二酰辅酶A以调控CPT1和脂肪生成中的假定作用一致。此外，在瘦人和肥胖受试者中，丙二酰辅酶A脱羧酶的表达均比脂肪酸合酶高约40倍，这表明在人类肌肉中，丙二酰辅酶A的主要命运是降解而非脂肪生成。没有其他基因显示出肥胖时mRNA含量增加的迹象，这表明在人类肥胖中，丙二酰辅酶A代谢可能存在选择性转录调控。
