Effect of gemfibrozil on apolipoprotein B secretion and diacylglycerol acyltransferase activity in human hepatoblastoma (HepG2) cells.
The mechanism of action of a widely used drug gemfibrozil to reduce triglycerides (TG) and apolipoprotein B (apo B) is incompletely understood. Using human hepatoblastoma (HepG2) cells, we examined the effect of gemfibrozil on apo B secretion and TG synthesis catalyzed by diacylglycerol acyltransferase (DGAT), primary processes associated with the secretion of LDL. Gemfibrozil significantly decreased apo B secretion by HepG2 cells. It decreased oleate-induced stimulation of apo B secretion, suggesting that gemfibrozil-mediated inhibition of apo B secretion may be dependent on the synthesis of TG catalyzed by DGAT. Pre-incubation of HepG2 cells with gemfibrozil (200-400 micromol/l for 48 h) significantly inhibited microsomal DGAT activity. When added directly to the DGAT assay system containing control microsomes, gemfibrozil significantly inhibited the activity of DGAT by 14-25%. Gemfibrozil (200-400 micromol/l) inhibited TG synthesis by 47-50% as measured by the incorporation of 3H-oleic acid into TG. The data indicate that gemfibrozil inhibits DGAT activity resulting in decreased synthesis of TG and its availability for apo B lipidation rendering it susceptible to intracellular apo B degradation leading to the decreased secretion. These in-vitro data suggest a novel additional mechanism by which gemfibrozil lowers plasma TG and atherogenic apo B lipoproteins in dyslipidemic patients.
Zhu
Daming
D
Cholesterol Research Center, Long Beach Department of Veterans Affairs Healthcare System and University of California, Irvine, 5901 E. Seventh Street (11-111I), Long Beach, CA 90822, USA.
Ganji
Shobha H
SH
Kamanna
Vaijinath S
VS
Kashyap
Moti L
ML
D000217:Acyltransferases / Q000187:drug effects / Q000378:metabolism*; D001055:Apolipoproteins B / Q000187:drug effects* / Q000378:metabolism*; D051048:Diacylglycerol O-Acyltransferase; D015248:Gemfibrozil / Q000494:pharmacology*; D018197:Hepatoblastoma; D006801:Humans; D008099:Liver / Q000166:cytology*; D008113:Liver Neoplasms; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D012680:Sensitivity and Specificity; D014280:Triglycerides / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D001055:Apolipoproteins B; D014280:Triglycerides; D000217:Acyltransferases; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase; D015248:Gemfibrozil