Ethanol down‐regulates the transcription of microsomal triglyceride transfer protein gene

Abstract

Microsomal triglyceride transfer protein (MTP) plays a central role in the assembly and secretion of apoB-containing lipoproteins. In this study, we investigated the effect of ethanol on the expression of the large subunit of MTP in a human liver hepatoma cell line, the HepG2 cells. Exposure of HepG2 cells to low concentrations of ethanol reduced MTP mRNA levels in a concentration- and time-dependent manner. The level of MTP mRNA decreased significantly (P<0.05, -26% relative to pretreatment control) when the concentration of ethanol in the culture medium was 50 ppm (0.005%, v/v). Maximal suppression (-50%) was observed at 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 activity and apoB secretion rate in HepG2 cells. To investigate the molecular mechanisms underlying this phenomenon, we examined the effect of ethanol on the promoter activity of the MTP gene. Transient transfection analysis of human MTP promoter-driven luciferase gene expression showed that ethanol down-regulates MTP promoter activity in a manner parallel to that observed for mRNA levels. Deletion analysis suggested that the MTP promoter sequence contains a negative ethanol response element -612 to -142 bp upstream of the transcription start site. To evaluate 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 intestinal MTP mRNA measured 3 h after dosing. Rats receiving 1 or 3 g/kg of ethanol exhibited substantially lower hepatic and intestinal MTP mRNA levels. Taken together, these results strongly suggest that ethanol can modulate the secretion of apoB-containing lipoproteins by down-regulating the expression of MTP large subunit, primarily through inhibiting the transcription of the MTP gene.

Inhibition of microsomal triglyceride transfer protein: Another mechanism for drug-induced steatosis in mice

“…[19][20][21] In the present study, ex vivo MTP activity was decreased within 4 hours of drug administration (Fig. 3), and this effect was reproduced in vitro when drugs were added to the liver homogenate of control mice (Fig.…”

Association between microsomal triglyceride transfer protein gene polymorphism and the biological features of liver steatosis in patients with Type II diabetes

“…It has been recently reported that ethanol, in addition to the well-known stimulation of hepatic lipogenesis, down-regulated MTP mRNA expression in HepG2 cells by a negative ethanol response element located near the ±493 G/T promoter polymorphism site (±642 to ±142 bp) [24]. It is however unlikely that this mechanism operated in our patients because none of them were heavy drinkers and the level of alcohol consumption was similar in the three genetic groups.…”

Lomitapide and Mipomersen

“…22,23 In vitro, alcohol has been shown to inhibit MTP activity. 26 Both alanine aminotransferase and aspartate aminotransferase were significantly correlated with maximum hepatic fat (P=0.0006 and P=0.0018, respectively) with r 2 values of 0.433 and 0.377, respectively. The changes in hepatic fat content were negatively correlated with the change in LDL-C levels.…”