Inhibition of hepatic gluconeogenesis and lipogenesis by benzoic acid, p-tert.-butylbenzoic acid, and a structurally related hypolipidemic agent SC-33459.
Inhibition of hepatic gluconeogenesis and lipogenesis by benzoic acid, p-tert.-butylbenzoic acid, and a structurally related hypolipidemic agent SC-33459.
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苯甲酸、对叔丁基苯甲酸和结构相关的降血脂剂 SC-33459 抑制肝脏糖异生和脂肪生成。
DOI：
10.1016/0003-9861(82)90014-5
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发表时间：
1982
影响因子：
3.9
通讯作者：
R. Harris
中科院分区：
文献类型：
--
作者：
S. Mccune;P. J. Durant;L. Flanders;R. Harris
研究发现，苯甲酸、对叔丁基苯甲酸和结构相关的降脂剂SC-33459能抑制禁食48小时大鼠肝细胞葡萄糖的合成，也能抑制饮食大鼠肝细胞的脂肪酸合成。葡萄糖合成不如脂肪酸合成敏感。苯甲酸是这两个过程中最无效的缓蚀剂；SC-33459和对叔丁基苯甲酸是非常有效的缓蚀剂，但效果相似。甘氨酸可拮抗苯甲酸对脂肪酸合成的抑制作用，但对对叔丁基苯甲酸的抑制作用无明显影响。辛酸可拮抗苯甲酸和对叔丁基苯甲酸的抑制作用。对叔丁基苯甲酸和SC-33459均能抑制[1-14C]油酸氧化成酮体和酸溶放射性产物。后一种作用需要用SC-33459预先孵育肝细胞，提示该化合物可能参与分解代谢。SC-33459是一种对叔丁基苯基衍生物，易经β氧化转化为对叔丁基苯甲酸。对叔丁基苯甲酸和SC-33459都显著降低了柠檬酸水平。三种化合物均能降低辅酶A和乙酰辅酶A的含量，增加中链酰辅酶A酯的含量。对叔丁基苯甲酸和SC-33459也增加了长链酰基辅酶A酯的含量。中链酰基-辅酶A水平的增加可能反映了苯甲酸生成苯甲酰辅酶A和间叔丁基苯甲酸和SC-33459生成对叔丁基苯甲酰辅酶A。这些化合物对葡萄糖和脂肪酸合成的抑制可能是由于对特定酶的影响或由于辅酶A的封存。
Benzoic acid,p-tert.-butylbenzoic acid, and a structurally related hypolipidemic agent SC-33459 were found to inhibit glucose synthesis by hepatocytes isolated from 48-h fasted rats as well as fatty acid synthesis by hepatocytes isolated from meal-fed rats. Glucose synthesis was less sensitive than fatty acid synthesis. Benzoic acid was the least effective inhibitor of both processes; SC-33459 andp-tert.-butylbenzoic acid were very potent inhibitors with similar efficacy. Glycine prevented the inhibition of fatty acid synthesis caused by benzoic acid, but had no effect on that caused byp-tert.-butylbenzoic acid. Octanoate opposed the inhibitory effects of both benzoic acid andp-tert.-butylbenzoic acid. Oxidation of [1-14C]oleate to ketone bodies and acid-soluble radioactive products was inhibited by bothp-tert.-butylbenzoic acid and SC-33459. Preincubation of hepatocytes with SC-33459 was required for the latter effect, suggesting catabolism of this compound may be involved. SC-33459 is ap-tert.-butylphenyl derivative which should be readily converted top-tert.-butylbenzoic acid by β oxidation. Bothp-tert.-butylbenzoic acid and SC-33459 decreased citrate levels dramatically. All three compounds reduced CoA and acetyl-CoA levels and increased medium-chain acyl-CoA ester levels.p-tert.-Butylbenzoic acid and SC-33459 also increased long-chain acyl-CoA ester levels. The increase in medium-chain acyl-CoA levels presumably reflects benzoyl-CoA formation from benzoic acid andp-tert.-butylbenzoyl-CoA formation fromp-tert.-butylbenzoic acid and SC-33459. Inhibition of glucose and fatty acid synthesis by these compounds may be due to effects on specific enzymes or to CoA sequestration.