Berge R K, Aarsland A, Kryvi H, Bremer J, Aarsaether N
Laboratory of Clinical Biochemistry, University of Bergen, Haukeland Sykehus, Norway.
Biochem Pharmacol. 1989 Nov 15;38(22):3969-79. doi: 10.1016/0006-2952(89)90676-x.
The activity of key enzymes involved in oxidation and esterification of long-chain fatty acids was investigated after male Wistar rats were treated with different doses of sulfur substituted fatty acid analogues, 1,10-bis(carboxymethylthiodecane) (BCMTD, non-beta-oxidizable and non-omega-oxidizable), 1-mono(carboxymethylthiotetradecane) (CMTTD, trivial name, alkylthio acetic acid, non-beta-oxidizable) and 1-mono(carboxyethylthiotetradecane) (CETTD trivial name, alkylthio propionic acid, beta-oxidizable). The sulfur substituted dicarboxylic acid and the alkylthio acetic acid induced in a dose-dependent manner the mitochondrial, microsomal and especially the peroxisomal palmitoyl-CoA synthetase activity, the mitochondrial and cytosolic palmitoyl-CoA hydrolase activity, the mitochondrial and especially the microsomal glycerophosphate acyltransferase activity and the peroxisomal beta-oxidation, especially revealed in the microsomal fraction. Morphometric analysis of randomly selected hepatocytes revealed that BCMTD and CMTTD treatment increased the number, size and volume fraction of peroxisomes and mitochondria. Thus, the observed changes in the specific activity of fatty acid metabolizing enzymes with multiple subcellular localization can partly be explained as an effect of changes in the s-values of the organelles as proliferation of mitochondria and peroxisomes occurred. The most striking effect of the alkylthio propionic acid was the formation of numerous fat droplets in the liver cells and enhancement of the hepatic triglyceride level. This was in contrast to BCMTD treatment which decreased the hepatic triglyceride content. In conclusion, the results provide evidence that administration of non-beta-oxidizable fatty acid analogues had much higher in vivo potency in inducing hepatomegaly and key enzymes involved in fatty acid metabolism, including proliferation of peroxisomes and mitochondria than is exhibited in the beta-oxidizable, alkylthio propionic acid. Moreover, the dicarboxylic acid was apparently three to six times more potent than the alkylthio acetic acid in inducing peroxisomal beta-oxidation and peroxisome proliferation when considered on a mumol/day basis. As palmitic acid and hexadecanedioic acid only marginally affected these hepatic responses, it is conceivable that the potency of the selected compounds as proliferators of peroxisomes and inducers of the associated enzymes depends on their accessibility for beta-oxidation.
在用不同剂量的硫取代脂肪酸类似物（1,10 - 双（羧甲基硫代癸烷）（BCMTD，不可β氧化且不可ω氧化）、1 - 单（羧甲基硫代十四烷）（CMTTD，俗名烷基硫代乙酸，不可β氧化）和1 - 单（羧乙基硫代十四烷）（CETTD，俗名烷基硫代丙酸，可β氧化））处理雄性Wistar大鼠后，对参与长链脂肪酸氧化和酯化的关键酶的活性进行了研究。硫取代的二羧酸和烷基硫代乙酸以剂量依赖性方式诱导线粒体、微粒体尤其是过氧化物酶体棕榈酰辅酶A合成酶活性、线粒体和胞质棕榈酰辅酶A水解酶活性、线粒体尤其是微粒体甘油磷酸酰基转移酶活性以及过氧化物酶体β氧化，尤其在微粒体部分表现明显。对随机选择的肝细胞进行形态计量分析表明，BCMTD和CMTTD处理增加了过氧化物酶体和线粒体的数量、大小和体积分数。因此，观察到的具有多个亚细胞定位的脂肪酸代谢酶比活性的变化，部分可以解释为细胞器s值变化的影响，因为线粒体和过氧化物酶体发生了增殖。烷基硫代丙酸最显著的作用是在肝细胞中形成大量脂滴并提高肝脏甘油三酯水平。这与BCMTD处理降低肝脏甘油三酯含量形成对比。总之，结果提供了证据，表明给予不可β氧化的脂肪酸类似物在诱导肝肿大和参与脂肪酸代谢的关键酶方面，包括过氧化物酶体和线粒体的增殖，其体内效力比可β氧化的烷基硫代丙酸高得多。此外，当以μmol/天为基础考虑时，二羧酸在诱导过氧化物酶体β氧化和过氧化物酶体增殖方面的效力明显比烷基硫代乙酸高三到六倍。由于棕榈酸和十六烷二酸对这些肝脏反应的影响很小，可以想象所选化合物作为过氧化物酶体增殖剂和相关酶诱导剂的效力取决于它们进行β氧化的可及性。
