Activation of Carbohydrate Response Element-Binding Protein by Ethanol

Abstract

Carbohydrate response element binding protein (ChREBP) is a transcription factor involved in hepatic lipogenesis. Its function is in part under the control of AMP-activated protein kinase (AMPK) and protein phosphatase 2A (PP2A). Given known effects of ethanol on AMPK and PP2A, it is plausible that ethanol might enhance fatty acid synthesis by increasing the activity of ChREBP. We hypothesized that another potential pathway of ethanol-induced hepatic steatosis is mediated by activation of ChREBP. Methods The effects of ethanol on ChREBP were assessed in hepatoma cells and in C57BL/6J mice fed with the Lieber-DeCarli diet. Results When the cells were exposed to ethanol (50 mM) for 24 hrs, the activity of a liver pyruvate kinase (LPK) promoter-luciferase reporter was increased by ~4-fold. Ethanol feeding of mice resulted in the translocation of ChREBP from cytosol to the nucleus. PP2A activity was increased in the liver of ethanol-fed mice by 22%. We found no difference in the levels of hepatic Xu-5-P between ethanol-fed mice and controls. Transfection of a constitutively active AMPK expression plasmid suppressed the basal activity of the LPK luciferase reporter and abolished the effect of ethanol on the reporter activity. However, transfection of rat hepatoma cells with a dominant negative AMPK expression plasmid induced basal LPK luciferase activity by only ~20%. The effect of ethanol on ChREBP was attenuated in the presence of okadaic acid, an inhibitor of PP2A. Conclusions The effects of ethanol on AMPK and PP2A may result in activation of ChREBP, providing another potential mechanism for ethanol-induced hepatic steatosis. However, additional okadaic acid-insensitive effects appear to be important as well.

Influence of fat/carbohydrate ratio on progression of fatty liver disease and on development of osteopenia in male rats fed alcohol via total enteral nutrition (TEN)

“…In contrast, we report that ethanol treatment increased hepatic accumulation of ChREBP which could drive increased transcription of FASN and ACC-1. These data are consistent with a recent report from Liangpunsakul et al (2013) demonstrating increased nuclear accumulation of ChREBP in ethanol-treated hepatoma cells in vitro and in ethanol-fed mice.…”

Ethanol-induced hepatic steatosis is modulated by glycogen level in the liver

“…that controls transcription of a range of genes involved in free fatty acid transport and oxidation. Recently, it was discovered that the activity ChREBP, an important transcription factor for de novo fatty acid synthesis ( 22 ), is elevated by alcohol exposure ( 24,25 ). In our experimental setting, we found that the mRNA level of ChREBP was not increased by EtOH treatment.…”

Novel role for carbohydrate responsive element binding protein in the control of ethanol metabolism and susceptibility to binge drinking

“…Because regulation by phosphorylation/dephosphorylation was recently described for ChREBP in response to chronic EtOH consumption, we measured levels of Ser‐196 ChREBP phosphorylation, a residue previously shown to be a target of protein kinase A during fasting and dephosphorylated in response to glucose metabolism activation http://onlinelibrary.wiley.com/doi/10.1002/hep.27778/suppinfo. Phosphorylation levels of ChREBP Ser‐196 were not different in liver lysates from DM‐ or EtOH‐treated groups http://onlinelibrary.wiley.com/doi/10.1002/hep.27778/suppinfo, suggesting that this posttranslational regulation was not a major mechanism of ChREBP activation in response to binge drinking.…”