Inhibition of long-chain acyl-CoA synthetase by the peroxisome proliferator perfluorodecanoic acid in rat hepatocytes.
Inhibition of long-chain acyl-CoA synthetase by the peroxisome proliferator perfluorodecanoic acid in rat hepatocytes.
复制标题
大鼠肝细胞中过氧化物酶体增殖剂全氟癸酸对长链酰基辅酶A合成酶的抑制。
DOI：
10.1016/0006-2952(91)90716-i
复制
发表时间：
1991
影响因子：
5.8
通讯作者：
Peterson,RE
中科院分区：
文献类型：
--
作者：
VandenHeuvel,JP;Kuslikis,BI;Shrago,E;Peterson,RE
全氟癸酸(PFDA)是一种强有力的过氧化物酶增殖剂，已知会影响大鼠的肝脏脂质代谢。在分离的大鼠肝细胞悬液以及大鼠肝线粒体和微粒体中检测了PFDA对脂肪酸利用的影响。当1 mM PFDA与肝细胞孵育时，PFDA抑制棕榈酸的氧化，但不抑制辛酸或丙酮酸的氧化。在此PFDA浓度下，棕榈酸的酯化反应也减少到三酰甘油。在1 mM PFDA孵育的肝细胞中，脂肪酸氧化和酯化所必需的长链酰辅酶A合成酶(ACS)的活性降低。肉碱棕榈酰基转移酶(CPT)是氧化长链脂肪酸的重要酶，在该浓度的PFDA孵育的肝细胞中不发生变化。在大鼠肝线粒体中，PFDA浓度显著降低(P<；0.01)，但对CPT活性无影响。PFDA对肝线粒体和微生物体制剂的抑制作用相似。在与PFDA孵育的线粒体中，对于底物棕榈酸和辅酶A，ACS的抑制似乎是非竞争性的。然而，PFDA对ACS的抑制作用似乎是与该酶的ATP结合部位竞争的。检测了几种链长的全氟化脂肪酸抑制线粒体ACS的能力。短链全氟化脂肪酸(全氟固有酸和-丁酸)不能抑制ACS的活性。然而，在分离的线粒体中，发现中链全氟酸(全氟辛酸、-厌氧酸和-癸酸)是ACS的有效抑制剂。抑制性冠脉综合征是否与PFDA诱导的过氧化酶体增殖和体内脂质代谢改变有关尚不清楚。
Perfluorodecanoic acid (PFDA) is a potent peroxisome proliferator and is known to affect hepatic lipid metabolism in rats. The effects of PFDA on fatty acid utilization were examined in isolated rat hepatocyte suspensions and in rat liver mitochondria and microsomes. PFDA inhibited the oxidation of palmitic acid but not octanoic or pyruvic acids when hepatocytes were incubated with 1 mM PFDA. At this PFDA concentration the esterification of palmitic acid into triacylglycerols was also reduced. The activity of long-chain acyl-CoA synthetase (ACS), an enzyme essential for both oxidation and esterification of fatty acids, was reduced in hepatocytes incubated with 1 mM PFDA. Carnitine palmitoyltransferase (CPT), an important enzyme for the oxidation of long-chain fatty acids, was not altered in hepatocytes incubated with this PFDA concentration. In rat liver mitochondria, palmitate oxidation and ACS activity were reduced significantly (P<0.01) at a PFDA concentration that had no effect on CPT activity. The inhibition of ACS by PFDA was similar in liver mitochondria and microsome preparations. In mitochondria incubated with PFDA, the inhibition of ACS appears to be noncompetitive for the substrates palmitic acid and CoA. However, the ACS inhibition by PFDA appeared to be competitive for the ATP binding site of the enzyme. Several chain length perfluorinated fatty acids were examined for their ability to inhibit mitochondrial ACS. Short-chain perfluorinated fatty acids (perfluoroproprionic and -butyric acid) did not inhibit ACS activity. However, medium-chain perfluorinated acids (perfluorooctanoic, -ananoic and -decanoic acid) were found to be potent inhibitors of ACS in isolated mitochondria. Whether ACS inhibition is causally related to PFDA-induced peroxisome proliferation and altered lipid metabolism seenin vivois yet to be determined.