Relationship between hepatic mitochondrial functions in vivo and in vitro in rats with carbon tetrachloride-induced liver cirrhosis
Relationship between hepatic mitochondrial functions in vivo and in vitro in rats with carbon tetrachloride-induced liver cirrhosis
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DOI：
10.1016/s0168-8278(00)80362-1
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发表时间：
2000-08-01
影响因子：
25.7
通讯作者：
Krähenbühl, S
中科院分区：
文献类型：
--
作者：
Krähenbühl, L;Ledermann, M;Krähenbühl, S
背景/目的：四氯化碳（CCl4）诱导肝硬化大鼠肝脏线粒体代谢能力受损。这些研究仅仅是为了找出苯甲酸盐和/或棕榈酸盐是否适合作为评估活体肝脏线粒体功能的底物。方法:通过监测肝硬化大鼠和对照组大鼠尿中棘酸盐的排泄和(CO2)-C-14的呼出，分别评估了苯甲酸酯和1-C-14-棕榈酸酯的体内代谢（每组8只），分离肝脏线粒体，并通过先前发表的方法进行了苯甲酸酯和棕榈酸酯的体外代谢。肝脏线粒体含量通过肝细胞体积的体学分析和生化测定来评估。利用柠檬酸合酶的活性。结果:在肝硬化大鼠中，口服苯甲酸酯后，肝脏中马粪酸的排泄量减少（24小时内给药剂量为64+/- 15% vs 85+/-14%），并与分离的线粒体中马粪酸的形成呈线性相关。肝硬化大鼠肝线粒体中苯甲酰辅酶a合成酶和苯甲酰辅酶a：甘氨酸n -酰基转移酶的活性仅降低了约60%，辅酶a含量降低了50%，解释了马粪酸形成受损。腹腔注射1-C-14-棕榈酸酯后，肝硬化大鼠(CO2)-C-14呼出峰值降低44%，(CO2)-C-14呼出时间曲线下面积降低34%，(CO2)-C-14呼出峰值与离体线粒体中棕榈酰肉碱的氧化代谢呈线性相关，体内苯甲酸酯和棕榈酸酯代谢均与肝细胞体积分数呈线性相关。肝硬化大鼠每肝和每肝的线粒体蛋白含量均降低，但与对照大鼠的每体积肝细胞含量相等。结论：棕榈酸酯和苯甲酸酯的体内代谢反映了ccl4诱导肝硬化大鼠的肝脏线粒体功能，ccl4诱导肝硬化大鼠的肝脏线粒体功能受损，主要是由于每肝线粒体体积减少和剩余线粒体代谢受损。与继发性胆汁性肝硬化大鼠相比，ccl4诱导的肝硬化大鼠没有肝脏线粒体增殖，以抵消线粒体功能的降低。
Background/Aims: The metabolic capacity of liver mitochondria is impaired in rats with carbon tetrachloride (CCl4)-induced cirrhosis. These studies mere performed to find out whether benzoate and/or palmitate are suitable substrates for assessing hepatic mitochondrial function in vivo.Methods: In vivo metabolism of benzoate and 1-C-14-palmitate mas assessed by monitoring urinary excretion of hippurate and exhalation of (CO2)-C-14, respectively, in cirrhotic and control rats (n=8 for each group), Isolation of liver mitochondria, and in vitro benzoate and palmitate metabolism mere performed by methods published previously The hepatic content of mitochondria was assessed by stereological analysis of the volume of hepatocytes and by biochemical determination, using the activity of citrate synthase.Results: Renal excretion of hippurate following i.p. administration of benzoate was reduced in cirrhotic rats (64+/-15 vs. 85+/-14% of administered dose over 24 h), and showed a linear correlation with hippurate formation by isolated mitochondria, The activities of benzoyl-CoA synthase and benzoyl-CoA:glycine N-acyltransferase mere reduced by approximately 60%, and the coenzyme A content by 50% in hepatic mitochondria from cirrhotic rats, explaining impaired hippurate formation, Peak exhalation of (CO2)-C-14 after i.p, administration of 1-C-14-palmitate was reduced by 44% and the area under the (CO2)-C-14 exhalation-time curve by 34% in cirrhotic rats, Peak (CO2)-C-14 exhalation revealed a linear correlation with oxidative metabolism of palmitoylcarnitine in isolated mitochondria, Both in vivo benzoate and palmitate metabolism showed a linear correlation with the volume fraction of hepatocytes, The mitochondrial protein content mas reduced in cirrhotic rats per g liver and per liver but equal to control rats per volume of hepatocytes.Conclusions: In vivo metabolism of both palmitate and benzoate reflects hepatic mitochondrial function in rats with CCl4-induced cirrhosis, Hepatic mitochondrial function is impaired in rats with CCl4-induced cirrhosis due to both reduced mitochondrial volume per liver and impaired metabolism of the remaining mitochondria. In contrast to rats with secondary biliary cirrhosis, rats with CCl4-induced cirrhosis showed no hepatic mitochondrial proliferation to counteract reduced mitochondrial function.