The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor α is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver

Andrea Galli, Jane Pinaire, Monika Fischer, Ryan Dorris, David Crabb

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

Fatty acids are ligands for the peroxisome proliferator-activated receptor α (PPARα). Fatty acid levels are increased in liver during the metabolism of ethanol and might be expected to activate PPARα. However, ethanol inhibited PPARα activation of a reporter gene in H4IIEC3 hepatoma cells expressing alcohol-metabolizing enzymes but not in CV-1 cells, which lack these enzymes. Ethanol also reduced the ability of the PPARα ligand WY14,643 to activate reporter constructs in the hepatoma cells or cultured rat hepatocytes. This effect of ethanol was abolished by the alcohol dehydrogenase inhibitor 4-methylpyrazole and augmented by the aldehyde dehydrogenase inhibitor cyanamide, indicating that acetaldehyde was responsible for the action of ethanol. PPARα/retinoid X receptor extracted from hepatoma cells exposed to ethanol or acetaldehyde bound poorly to an oligonucleotide containing peroxisome proliferator response elements. This effect was also blocked by 4-methylpyrazole and augmented by cyanamide. Furthermore, in vitro translated PPARα exposed to acetaldehyde failed to bind DNA. Thus, ethanol metabolism blocks transcriptional activation by PPARα, in part due to impairment of its ability to bind DNA. This effect of ethanol may promote the development of alcoholic fatty liver and other hepatic consequences of alcohol abuse.

Original languageEnglish
Pages (from-to)68-75
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number1
DOIs
StatePublished - Jan 5 2001

Fingerprint

Peroxisome Proliferator-Activated Receptors
Fatty Liver
Metabolism
Liver
Ethanol
DNA
Acetaldehyde
Cyanamide
Hepatocellular Carcinoma
Aptitude
Fatty Acids
Chemical activation
Alcoholic Fatty Liver
Alcohols
Peroxisome Proliferators
Ligands
Retinoid X Receptors
Aldehyde Dehydrogenase
Alcohol Dehydrogenase
Response Elements

ASJC Scopus subject areas

  • Biochemistry

Cite this

@article{bded551da8ef48b18659b42142ffb9f9,
title = "The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor α is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver",
abstract = "Fatty acids are ligands for the peroxisome proliferator-activated receptor α (PPARα). Fatty acid levels are increased in liver during the metabolism of ethanol and might be expected to activate PPARα. However, ethanol inhibited PPARα activation of a reporter gene in H4IIEC3 hepatoma cells expressing alcohol-metabolizing enzymes but not in CV-1 cells, which lack these enzymes. Ethanol also reduced the ability of the PPARα ligand WY14,643 to activate reporter constructs in the hepatoma cells or cultured rat hepatocytes. This effect of ethanol was abolished by the alcohol dehydrogenase inhibitor 4-methylpyrazole and augmented by the aldehyde dehydrogenase inhibitor cyanamide, indicating that acetaldehyde was responsible for the action of ethanol. PPARα/retinoid X receptor extracted from hepatoma cells exposed to ethanol or acetaldehyde bound poorly to an oligonucleotide containing peroxisome proliferator response elements. This effect was also blocked by 4-methylpyrazole and augmented by cyanamide. Furthermore, in vitro translated PPARα exposed to acetaldehyde failed to bind DNA. Thus, ethanol metabolism blocks transcriptional activation by PPARα, in part due to impairment of its ability to bind DNA. This effect of ethanol may promote the development of alcoholic fatty liver and other hepatic consequences of alcohol abuse.",
author = "Andrea Galli and Jane Pinaire and Monika Fischer and Ryan Dorris and David Crabb",
year = "2001",
month = "1",
day = "5",
doi = "10.1074/jbc.M008791200",
language = "English",
volume = "276",
pages = "68--75",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "1",

}

TY - JOUR

T1 - The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor α is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver

AU - Galli, Andrea

AU - Pinaire, Jane

AU - Fischer, Monika

AU - Dorris, Ryan

AU - Crabb, David

PY - 2001/1/5

Y1 - 2001/1/5

N2 - Fatty acids are ligands for the peroxisome proliferator-activated receptor α (PPARα). Fatty acid levels are increased in liver during the metabolism of ethanol and might be expected to activate PPARα. However, ethanol inhibited PPARα activation of a reporter gene in H4IIEC3 hepatoma cells expressing alcohol-metabolizing enzymes but not in CV-1 cells, which lack these enzymes. Ethanol also reduced the ability of the PPARα ligand WY14,643 to activate reporter constructs in the hepatoma cells or cultured rat hepatocytes. This effect of ethanol was abolished by the alcohol dehydrogenase inhibitor 4-methylpyrazole and augmented by the aldehyde dehydrogenase inhibitor cyanamide, indicating that acetaldehyde was responsible for the action of ethanol. PPARα/retinoid X receptor extracted from hepatoma cells exposed to ethanol or acetaldehyde bound poorly to an oligonucleotide containing peroxisome proliferator response elements. This effect was also blocked by 4-methylpyrazole and augmented by cyanamide. Furthermore, in vitro translated PPARα exposed to acetaldehyde failed to bind DNA. Thus, ethanol metabolism blocks transcriptional activation by PPARα, in part due to impairment of its ability to bind DNA. This effect of ethanol may promote the development of alcoholic fatty liver and other hepatic consequences of alcohol abuse.

AB - Fatty acids are ligands for the peroxisome proliferator-activated receptor α (PPARα). Fatty acid levels are increased in liver during the metabolism of ethanol and might be expected to activate PPARα. However, ethanol inhibited PPARα activation of a reporter gene in H4IIEC3 hepatoma cells expressing alcohol-metabolizing enzymes but not in CV-1 cells, which lack these enzymes. Ethanol also reduced the ability of the PPARα ligand WY14,643 to activate reporter constructs in the hepatoma cells or cultured rat hepatocytes. This effect of ethanol was abolished by the alcohol dehydrogenase inhibitor 4-methylpyrazole and augmented by the aldehyde dehydrogenase inhibitor cyanamide, indicating that acetaldehyde was responsible for the action of ethanol. PPARα/retinoid X receptor extracted from hepatoma cells exposed to ethanol or acetaldehyde bound poorly to an oligonucleotide containing peroxisome proliferator response elements. This effect was also blocked by 4-methylpyrazole and augmented by cyanamide. Furthermore, in vitro translated PPARα exposed to acetaldehyde failed to bind DNA. Thus, ethanol metabolism blocks transcriptional activation by PPARα, in part due to impairment of its ability to bind DNA. This effect of ethanol may promote the development of alcoholic fatty liver and other hepatic consequences of alcohol abuse.

UR - http://www.scopus.com/inward/record.url?scp=0035808410&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035808410&partnerID=8YFLogxK

U2 - 10.1074/jbc.M008791200

DO - 10.1074/jbc.M008791200

M3 - Article

VL - 276

SP - 68

EP - 75

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 1

ER -