Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals
Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals
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DOI：
10.1074/jbc.m304481200
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发表时间：
2003-09-26
影响因子：
4.8
通讯作者：
Eisenbeis, SA
中科院分区：
文献类型：
--
作者：
Harwood, HJ;Petras, SF;Eisenbeis, SA
抑制乙酰辅酶A羧化酶（ACC），其结果是抑制脂肪酸合成和刺激脂肪酸氧化，有可能有利地影响与代谢综合征相关的心血管危险因素的数量。为了达到最大的效果，ACC抑制剂应该抑制脂肪生成组织同工酶（ACC 1）和氧化组织同工酶（ACC 2）。在此，我们描述了CP-610431的生化和急性生理特性，CP-610431是一种通过高通量抑制筛选鉴定的同工酶非选择性ACC抑制剂，CP-640186是一种具有改善代谢稳定性的类似物。CP-610431抑制ACC 1和ACC 2，IC（50）值约为50 nM。抑制作用是可逆的，相对于ATP是非竞争性的，相对于碳酸氢盐、乙酰辅酶A和柠檬酸盐是非竞争性的，表明与酶促羧基转移反应的相互作用。CP-610431还抑制HepG 2细胞（ACC 1）中脂肪酸合成、甘油三酯（TG）合成、TG分泌和载脂蛋白B分泌，EC（50）为1.6、1.8、3.0和5.7 μ M，但不影响胆固醇合成或载脂蛋白C III分泌。CP-640186对两种同工酶的抑制IC（50）均为55 nM，但对HepG 2细胞脂肪酸和TG合成的抑制作用比CP-610431强2-3倍。CP-640186还刺激C2 C12细胞（ACC 2）和大鼠上滑车肌条中的脂肪酸氧化，EC（50）为57 nM和1.3 μ M。在大鼠中，CP-640186降低了肝脏、比目鱼肌、四头肌和心肌丙二酰辅酶A，艾德（50）s为55、6、15和8 mg/kg。因此，CP-640186在艾德（50）为13、11和4 mg/kg时抑制大鼠、CD 1小鼠和ob/ob小鼠的脂肪酸合成，并刺激大鼠全身脂肪酸氧化，其ED 50与30 mg/kg相似。综上所述，这些观察结果表明，同工酶非选择性ACC抑制有可能有利地影响与代谢综合征相关的危险因素。
Inhibition of acetyl-CoA carboxylase (ACC), with its resultant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect the multitude of cardiovascular risk factors associated with the metabolic syndrome. To achieve maximal effectiveness, an ACC inhibitor should inhibit both the lipogenic tissue isozyme (ACC1) and the oxidative tissue isozyme (ACC2). Herein, we describe the biochemical and acute physiological properties of CP-610431, an isozyme-nonselective ACC inhibitor identified through high throughput inhibition screening, and CP-640186, an analog with improved metabolic stability. CP-610431 inhibited ACC1 and ACC2 with IC(50)s of similar to50 nM. Inhibition was reversible, uncompetitive with respect to ATP, and non-competitive with respect to bicarbonate, acetyl-CoA, and citrate, indicating interaction with the enzymatic carboxyl transfer reaction. CP-610431 also inhibited fatty acid synthesis, triglyceride (TG) synthesis, TG secretion, and apolipoprotein B secretion in HepG2 cells ( ACC1) with EC(50)s of 1.6, 1.8, 3.0, and 5.7 muM, without affecting either cholesterol synthesis or apolipoprotein CIII secretion. CP-640186, also inhibited both isozymes with IC(50)s of similar to55 nM but was 2-3 times more potent than CP-610431 in inhibiting HepG2 cell fatty acid and TG synthesis. CP-640186 also stimulated fatty acid oxidation in C2C12 cells ( ACC2) and in rat epitrochlearis muscle strips with EC(50)s of 57 nM and 1.3 muM. In rats, CP-640186 lowered hepatic, soleus muscle, quadriceps muscle, and cardiac muscle malonyl-CoA with ED(50)s of 55, 6, 15, and 8 mg/kg. Consequently, CP-640186 inhibited fatty acid synthesis in rats, CD1 mice, and ob/ob mice with ED(50)s of 13, 11, and 4 mg/kg, and stimulated rat whole body fatty acid oxidation with an ED50 of similar to30 mg/kg. Taken together, These observations indicate that isozyme-nonselective ACC inhibition has the potential to favorably affect risk factors associated with the metabolic syndrome.