Lettéron Philippe, Sutton Angela, Mansouri Abdellah, Fromenty Bernard, Pessayre Dominique
Faculté de Médecine Xavier Bichat, INSERM U481, Paris, France.
Hepatology. 2003 Jul;38(1):133-40. doi: 10.1053/jhep.2003.50309.
Although many steatogenic drugs inhibit mitochondrial fatty acid beta-oxidation, limited information is available on possible effects on hepatic lipoprotein secretion. In the endoplasmic reticulum (ER) lumen, microsomal triglyceride transfer protein (MTP) lipidates apolipoprotein B (Apo B), to form triglyceride (TG)-rich very low density lipoprotein (VLDL) particles, which follow vesicular flow to the plasma membrane to be secreted, whereas incompletely lipidated Apo B particles are partly degraded. We studied hepatic MTP activity, the lipoproteins present in the ER lumen, and hepatic lipoprotein secretion 4 hours after administration of a single dose of amineptine (1 mmol/kg), amiodarone (1 mmol/kg), doxycycline (0.25 mmol/kg), tetracycline (0.25 mmol/kg), tianeptine (0.5 mmol/kg), or pirprofen (2 mmol/kg) in mice. These various doses have been shown previously to markedly inhibit fatty acid oxidation after a single dose, and to trigger steatosis either after repeated doses (doxycycline) or a single dose (other compounds) in mice. In the present study, amineptine, amiodarone, pirprofen, tetracycline, and tianeptine, but not doxycycline, inhibited MTP activity in vitro, decreased ex vivo MTP activity in the hepatic homogenate of treated mice, decreased TG in the luminal VLDL fraction of hepatic microsomes of treated mice, and decreased in vivo hepatic lipoprotein secretion (TG and Apo B). In conclusion, several steatogenic drugs inhibit not only mitochondrial beta-oxidation, as previously shown, but also MTP activity, Apo B lipidation into TG-rich VLDL particles, and hepatic lipoprotein secretion. Drugs with these dual effects may be more steatogenic than drugs acting only on beta-oxidation or only MTP.
尽管许多致脂肪变性的药物会抑制线粒体脂肪酸β-氧化，但关于其对肝脏脂蛋白分泌可能产生的影响，目前可用信息有限。在内质网（ER）腔中，微粒体甘油三酯转移蛋白（MTP）使载脂蛋白B（Apo B）脂化，形成富含甘油三酯（TG）的极低密度脂蛋白（VLDL）颗粒，这些颗粒沿着囊泡流至质膜后被分泌出去，而未完全脂化的Apo B颗粒则会部分降解。我们研究了单次给予小鼠胺苯环庚烯（1 mmol/kg）、胺碘酮（1 mmol/kg）、强力霉素（0.25 mmol/kg）、四环素（0.25 mmol/kg）、噻奈普汀（0.5 mmol/kg）或吡洛芬（2 mmol/kg）4小时后肝脏MTP活性、ER腔中存在的脂蛋白以及肝脏脂蛋白分泌情况。先前已表明，这些不同剂量的药物单次给药后可显著抑制脂肪酸氧化，并且在小鼠重复给药（强力霉素）或单次给药（其他化合物）后可引发脂肪变性。在本研究中，胺苯环庚烯、胺碘酮、吡洛芬、四环素和噻奈普汀（而非强力霉素）在体外抑制MTP活性，降低处理后小鼠肝脏匀浆中的体外MTP活性，降低处理后小鼠肝脏微粒体腔VLDL部分中的TG含量，并降低体内肝脏脂蛋白分泌（TG和Apo B）。总之，几种致脂肪变性的药物不仅如先前所示抑制线粒体β-氧化，还抑制MTP活性、Apo B脂化为富含TG的VLDL颗粒以及肝脏脂蛋白分泌。具有这些双重作用的药物可能比仅作用于β-氧化或仅作用于MTP的药物更易导致脂肪变性。
