The regulation of acetyl-CoA carboxylase - A potential target for the action of hypolipidemic agents
The regulation of acetyl-CoA carboxylase - A potential target for the action of hypolipidemic agents
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DOI：
10.1016/s0065-2571(98)00016-8
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发表时间：
1999-01-01
期刊：
影响因子：
--
通讯作者：
Hemingway, CJ
中科院分区：
文献类型：
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作者：
Munday, MR;Hemingway, CJ
ACC 以两种主要亚型 ACC1 或 ACC α 和 ACC2 或 ACC β 形式存在，有证据表明它们分别在用于脂肪酸合成的丙二酰辅酶 A 的产生和线粒体 β 氧化的控制中发挥不同的作用。 ACC α 可以在基因表达水平、酶的变构调节以及 AMP-PK 的可逆磷酸化水平上进行调节。新兴研究表明 ACC beta 也存在类似的调节机制。它通过 AMP-PK 磷酸化而在心脏和骨骼肌中失活，这一点已得到证实。 ACC 是某些降血脂药物（例如贝特类药物）的重要靶点。这不仅仅是因为 ACC α 抑制会减少 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)；这也是因为 ACC β 抑制会导致丙二酰辅酶 A 水平降低和脂肪酸氧化去抑制。将脂肪酸分配给氧化而不是酯化是贝特类降脂作用的一个重要方面。贝特类药物可以利用 ACC 调节的任何机制来减少活动。它们可以通过激活 PPAR α 来抑制 ACC 基因表达，而纤维酰辅酶 A 酯可以像 TOFyl-CoA 一样以变构方式抑制 ACC。然而，我们已经证明，吉非贝齐可在培养的大鼠肝细胞中快速灭活 ACC，这是由 AMP-PK 的激活和随后的 ACC 磷酸化介导的。最终结果是抑制肝脏脂肪酸合成，并可能激活β-氧化，酮体产生增加就证明了这一点。贝特类激活 AMP-PK 级联的机制、PPAR α 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使用是正在进行的研究领域。
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.