ETHANOL DOWN-REGULATES THE TRANSCRIPTION OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN GENE

Microsomal triglyceride transfer protein (MTP) plays a central role in the assembly and secretion of apoB-containing lipoproteins. In this s tudy, we investigated the effect of ethanol on the expression of the l arge subunit of MTP in a human liver hepatoma cell line, the HepG2 cel ls, Exposure of HepG2 cells to low concentrations of ethanol reduced M TP mRNA levels in a concentration-and time-dependent manner, The level of MTP mRNA decreased significantly (P < 0.05, -26% relative to pretr eatment control) when the concentration of ethanol in the culture medi um was 50 ppm (0.005%, v/v), Maximal suppression (-50%) was observed a t 100 ppm ethanol; the MTP mRNA levels remained at 50% of control when the ethanol concentration was raised to 10,000 ppm, Furthermore, a 10 -day ethanol treatment caused a significant 50% decrease in the MTP ac tivity and apoB secretion rate in HepG2 cells. To investigate the mole cular mechanisms underlying this phenomenon, we examined the effect of ethanol on the promoter activity of the MTP gene. Transient transfect ion analysis of human MTP promoter-driven luciferase gene expression s howed that ethanol down-regulates MTP promoter activity in a manner pa rallel to that observed for mRNA levels, Deletion analysis suggested t hat the MTP promoter sequence contains a negative ethanol response ele ment -612 to -142 bp upstream of the transcription start site, To eval uate the in vivo relevance of the effect of ethanol on MTP mRNA levels , rats were given a single oral dose of ethanol, with hepatic and inte stinal MTP mRNA measured 3 h after dosing, Rats receiving 1 or 3 g/kg of ethanol exhibited substantially lower hepatic and intestinal MTP mR NA levels, Taken together, these results strongly suggest that ethanol can modulate the secretion of apoB-containing lipoproteins by down-re gulating the expression of MTP large subunit, primarily through inhibi ting the transcription of the MTP gene.