Munday M R, Hemingway C J
Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University of London, UK.
Adv Enzyme Regul. 1999;39:205-34. doi: 10.1016/s0065-2571(98)00016-8.
ACC exists as two major isoforms ACC1 or ACC alpha, and ACC2 or ACC beta, and there is evidence that they play separate roles in the production of malonyl-CoA for fatty acid synthesis and the control of mitochondrial beta-oxidation, respectively. ACC alpha can be regulated at the level of gene expression, allosteric regulation of the enzyme, and reversible phosphorylation by AMP-PK. Emerging lines of research suggest that similar mechanisms of regulation exist for ACC beta. Its inactivation in heart and skeletal muscle through phosphorylation by AMP-PK is becoming well-established. ACC is an important target of certain hypolipidemic drugs such as the fibrates. This is not simply because ACC alpha inhibition decreases the synthesis of a lipid component of VLDL because fatty acids synthesized de novo in liver are not always major contributors to VLDL lipid (158); it is also because ACC beta inhibition leads to a decrease in malonyl-CoA levels and the disinhibition of fatty acid oxidation. Partitioning fatty acids towards oxidation and away from esterification is an important aspect of the lipid-lowering effects of fibrates. Fibrates could use any of the mechanisms of ACC regulation to decrease activity. They could repress ACC gene expression through the activation of PPAR alpha, and fibroyl-CoA esters could inhibit ACC allosterically just as TOFyl-CoA does. However, we have demonstrated a rapid inactivation of ACC in cultured rat hepatocytes by gemfibrozil that is mediated by activation of AMP-PK and the subsequent phosphorylation of ACC. The end result is the inhibition of hepatic fatty acid synthesis and a possible activation of beta-oxidation as evidenced by the increased production of ketone bodies. The mechanism through which fibrates activate the AMP-PK cascade, the role of PPAR alpha, the physiological responses of biosynthesis and oxidation and the use of these mechanisms by other hypolipidemic agents are areas of ongoing investigation.
乙酰辅酶A羧化酶（ACC）以两种主要同工型存在，即ACC1或ACCα，以及ACC2或ACCβ，有证据表明它们分别在脂肪酸合成的丙二酰辅酶A生成和线粒体β氧化的控制中发挥不同作用。ACCα可在基因表达水平、酶的变构调节以及AMP依赖的蛋白激酶（AMP-PK）的可逆磷酸化水平上受到调节。新出现的研究表明，ACCβ也存在类似的调节机制。通过AMP-PK磷酸化使其在心脏和骨骼肌中失活的现象已得到充分证实。ACC是某些降血脂药物（如贝特类药物）的重要靶点。这不仅仅是因为抑制ACCα会减少极低密度脂蛋白（VLDL）脂质成分的合成，因为肝脏中从头合成的脂肪酸并不总是VLDL脂质的主要贡献者（158）；还因为抑制ACCβ会导致丙二酰辅酶A水平降低以及脂肪酸氧化的去抑制。将脂肪酸导向氧化而非酯化是贝特类药物降血脂作用的一个重要方面。贝特类药物可以利用ACC调节的任何机制来降低其活性。它们可以通过激活过氧化物酶体增殖物激活受体α（PPARα）来抑制ACC基因表达，并且纤维酰辅酶A酯可以像TOFyl-CoA一样变构抑制ACC。然而，我们已经证明，吉非贝齐在培养的大鼠肝细胞中可通过激活AMP-PK以及随后ACC的磷酸化，使ACC快速失活。最终结果是抑制肝脏脂肪酸合成，并可能激活β氧化，酮体生成增加就证明了这一点。贝特类药物激活AMP-PK级联反应的机制、PPARα的作用、生物合成和氧化的生理反应以及其他降血脂药物对这些机制的利用，都是正在研究的领域。
