Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice.
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.
Lettéron
Philippe
P
Faculté de Médecine Xavier Bichat, INSERM U481, Paris, France.
Sutton
Angela
A
Mansouri
Abdellah
A
Fromenty
Bernard
B
Pessayre
Dominique
D
D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001055:Apolipoproteins B / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005234:Fatty Liver / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010666:Phenylpropionates / Q000494:pharmacology; D013010:Sonication; D013752:Tetracycline / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000929:Antidepressive Agents, Tricyclic; D001055:Apolipoproteins B; D002352:Carrier Proteins; D003986:Dibenzocycloheptenes; D004791:Enzyme Inhibitors; D008079:Lipoproteins, VLDL; D010666:Phenylpropionates; D013841:Thiazepines; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; C050504:tianeptine; C011597:amineptin; D013752:Tetracycline; D004318:Doxycycline; D000638:Amiodarone; C008924:pirprofen