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Inhibition of microsomal triglyceride transfer protein: Another mechanism for drug‐induced steatosis in mice
Author(s) -
Lettéron Philippe,
Sutton Angela,
Mansouri Abdellah,
Fromenty Bernard,
Pessayre Dominique
Publication year - 2003
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2003.50309
Subject(s) - very low density lipoprotein , microsomal triglyceride transfer protein , medicine , endocrinology , chemistry , triglyceride , steatosis , lipoprotein , microsome , apolipoprotein b , in vivo , doxycycline , pharmacology , biochemistry , cholesterol , biology , in vitro , microbiology and biotechnology , antibiotics
Although many steatogenic drugs inhibit mitochondrial fatty acid β‐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 β‐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 β‐oxidation or only MTP.