Peroxisome Proliferator-Activated Receptors α and γ are Linked with Alcohol Consumption in Mice and Withdrawal and Dependence in Humans

Yuri A. Blednov, Jillian M. Benavidez, Mendy Black, Laura B. Ferguson, Grant L. Schoenhard, Alison M. Goate, Howard Edenberg, Leah Wetherill, Victor Hesselbrock, Tatiana Foroud, R. Adron Harris

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Background: Peroxisome proliferator-activated receptor (PPAR) agonists reduce voluntary ethanol (EtOH) consumption in rat models and are promising therapeutics in the treatment for drug addictions. We studied the effects of different classes of PPAR agonists on chronic EtOH intake and preference in mice with a genetic predisposition for high alcohol consumption and then examined human genomewide association data for polymorphisms in PPAR genes in alcohol-dependent subjects. Methods: Two different behavioral tests were used to measure intake of 15% EtOH in C57BL/6J male mice: 24-hour 2-bottle choice and limited access (3-hour) 2-bottle choice, drinking in the dark. We measured the effects of pioglitazone (10 and 30 mg/kg), fenofibrate (50 and 150 mg/kg), GW0742 (10 mg/kg), tesaglitazar (1.5 mg/kg), and bezafibrate (25 and 75 mg/kg) on EtOH intake and preference. Fenofibric acid, the active metabolite of fenofibrate, was quantified in mouse plasma, liver, and brain by liquid chromatography tandem mass spectrometry. Data from a human genome-wide association study (GWAS) completed in the Collaborative Study on the Genetics of Alcoholism (COGA) were then used to analyze the association of single nucleotide polymorphisms (SNPs) in different PPAR genes (PPARA, PPARD, PPARG, and PPARGC1A) with 2 phenotypes: DSM-IV alcohol dependence (AD) and the DSM-IV criterion of withdrawal. Results: Activation of 2 isoforms of PPARs, α and γ, reduced EtOH intake and preference in the 2 different consumption tests in mice. However, a selective PPARδ agonist or a pan agonist for all 3 PPAR isoforms did not decrease EtOH consumption. Fenofibric acid, the active metabolite of the PPARα agonist fenofibrate, was detected in liver, plasma, and brain after 1 or 8 days of oral treatment. The GWAS from COGA supported an association of SNPs in PPARA and PPARG with alcohol withdrawal and PPARGC1A with AD but found no association for PPARD with either phenotype. Conclusions: We provide convergent evidence using both mouse and human data for specific PPARs in alcohol action. Reduced EtOH intake in mice and the genetic association between AD or withdrawal in humans highlight the potential for repurposing FDA-approved PPARα or PPARγ agonists for the treatment of AD.

Original languageEnglish
Pages (from-to)136-145
Number of pages10
JournalAlcoholism: Clinical and Experimental Research
Volume39
Issue number1
DOIs
StatePublished - Jan 1 2015

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Peroxisome Proliferator-Activated Receptors
Alcohol Drinking
Alcohols
Alcoholism
Association reactions
Fenofibrate
Genes
Polymorphism
pioglitazone
Genome-Wide Association Study
Bottles
Metabolites
Diagnostic and Statistical Manual of Mental Disorders
Liver
Single Nucleotide Polymorphism
Brain
Protein Isoforms
Nucleotides
Bezafibrate
Phenotype

Keywords

  • C57BL/6J
  • Fenofibrate
  • Fenofibric Acid
  • Genome-Wide Association Study
  • Pioglitazone
  • Tesag-litazar
  • Two-Bottle Choice

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

Peroxisome Proliferator-Activated Receptors α and γ are Linked with Alcohol Consumption in Mice and Withdrawal and Dependence in Humans. / Blednov, Yuri A.; Benavidez, Jillian M.; Black, Mendy; Ferguson, Laura B.; Schoenhard, Grant L.; Goate, Alison M.; Edenberg, Howard; Wetherill, Leah; Hesselbrock, Victor; Foroud, Tatiana; Adron Harris, R.

In: Alcoholism: Clinical and Experimental Research, Vol. 39, No. 1, 01.01.2015, p. 136-145.

Research output: Contribution to journalArticle

Blednov, YA, Benavidez, JM, Black, M, Ferguson, LB, Schoenhard, GL, Goate, AM, Edenberg, H, Wetherill, L, Hesselbrock, V, Foroud, T & Adron Harris, R 2015, 'Peroxisome Proliferator-Activated Receptors α and γ are Linked with Alcohol Consumption in Mice and Withdrawal and Dependence in Humans', Alcoholism: Clinical and Experimental Research, vol. 39, no. 1, pp. 136-145. https://doi.org/10.1111/acer.12610
Blednov, Yuri A. ; Benavidez, Jillian M. ; Black, Mendy ; Ferguson, Laura B. ; Schoenhard, Grant L. ; Goate, Alison M. ; Edenberg, Howard ; Wetherill, Leah ; Hesselbrock, Victor ; Foroud, Tatiana ; Adron Harris, R. / Peroxisome Proliferator-Activated Receptors α and γ are Linked with Alcohol Consumption in Mice and Withdrawal and Dependence in Humans. In: Alcoholism: Clinical and Experimental Research. 2015 ; Vol. 39, No. 1. pp. 136-145.
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abstract = "Background: Peroxisome proliferator-activated receptor (PPAR) agonists reduce voluntary ethanol (EtOH) consumption in rat models and are promising therapeutics in the treatment for drug addictions. We studied the effects of different classes of PPAR agonists on chronic EtOH intake and preference in mice with a genetic predisposition for high alcohol consumption and then examined human genomewide association data for polymorphisms in PPAR genes in alcohol-dependent subjects. Methods: Two different behavioral tests were used to measure intake of 15{\%} EtOH in C57BL/6J male mice: 24-hour 2-bottle choice and limited access (3-hour) 2-bottle choice, drinking in the dark. We measured the effects of pioglitazone (10 and 30 mg/kg), fenofibrate (50 and 150 mg/kg), GW0742 (10 mg/kg), tesaglitazar (1.5 mg/kg), and bezafibrate (25 and 75 mg/kg) on EtOH intake and preference. Fenofibric acid, the active metabolite of fenofibrate, was quantified in mouse plasma, liver, and brain by liquid chromatography tandem mass spectrometry. Data from a human genome-wide association study (GWAS) completed in the Collaborative Study on the Genetics of Alcoholism (COGA) were then used to analyze the association of single nucleotide polymorphisms (SNPs) in different PPAR genes (PPARA, PPARD, PPARG, and PPARGC1A) with 2 phenotypes: DSM-IV alcohol dependence (AD) and the DSM-IV criterion of withdrawal. Results: Activation of 2 isoforms of PPARs, α and γ, reduced EtOH intake and preference in the 2 different consumption tests in mice. However, a selective PPARδ agonist or a pan agonist for all 3 PPAR isoforms did not decrease EtOH consumption. Fenofibric acid, the active metabolite of the PPARα agonist fenofibrate, was detected in liver, plasma, and brain after 1 or 8 days of oral treatment. The GWAS from COGA supported an association of SNPs in PPARA and PPARG with alcohol withdrawal and PPARGC1A with AD but found no association for PPARD with either phenotype. Conclusions: We provide convergent evidence using both mouse and human data for specific PPARs in alcohol action. Reduced EtOH intake in mice and the genetic association between AD or withdrawal in humans highlight the potential for repurposing FDA-approved PPARα or PPARγ agonists for the treatment of AD.",
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T1 - Peroxisome Proliferator-Activated Receptors α and γ are Linked with Alcohol Consumption in Mice and Withdrawal and Dependence in Humans

AU - Blednov, Yuri A.

AU - Benavidez, Jillian M.

AU - Black, Mendy

AU - Ferguson, Laura B.

AU - Schoenhard, Grant L.

AU - Goate, Alison M.

AU - Edenberg, Howard

AU - Wetherill, Leah

AU - Hesselbrock, Victor

AU - Foroud, Tatiana

AU - Adron Harris, R.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background: Peroxisome proliferator-activated receptor (PPAR) agonists reduce voluntary ethanol (EtOH) consumption in rat models and are promising therapeutics in the treatment for drug addictions. We studied the effects of different classes of PPAR agonists on chronic EtOH intake and preference in mice with a genetic predisposition for high alcohol consumption and then examined human genomewide association data for polymorphisms in PPAR genes in alcohol-dependent subjects. Methods: Two different behavioral tests were used to measure intake of 15% EtOH in C57BL/6J male mice: 24-hour 2-bottle choice and limited access (3-hour) 2-bottle choice, drinking in the dark. We measured the effects of pioglitazone (10 and 30 mg/kg), fenofibrate (50 and 150 mg/kg), GW0742 (10 mg/kg), tesaglitazar (1.5 mg/kg), and bezafibrate (25 and 75 mg/kg) on EtOH intake and preference. Fenofibric acid, the active metabolite of fenofibrate, was quantified in mouse plasma, liver, and brain by liquid chromatography tandem mass spectrometry. Data from a human genome-wide association study (GWAS) completed in the Collaborative Study on the Genetics of Alcoholism (COGA) were then used to analyze the association of single nucleotide polymorphisms (SNPs) in different PPAR genes (PPARA, PPARD, PPARG, and PPARGC1A) with 2 phenotypes: DSM-IV alcohol dependence (AD) and the DSM-IV criterion of withdrawal. Results: Activation of 2 isoforms of PPARs, α and γ, reduced EtOH intake and preference in the 2 different consumption tests in mice. However, a selective PPARδ agonist or a pan agonist for all 3 PPAR isoforms did not decrease EtOH consumption. Fenofibric acid, the active metabolite of the PPARα agonist fenofibrate, was detected in liver, plasma, and brain after 1 or 8 days of oral treatment. The GWAS from COGA supported an association of SNPs in PPARA and PPARG with alcohol withdrawal and PPARGC1A with AD but found no association for PPARD with either phenotype. Conclusions: We provide convergent evidence using both mouse and human data for specific PPARs in alcohol action. Reduced EtOH intake in mice and the genetic association between AD or withdrawal in humans highlight the potential for repurposing FDA-approved PPARα or PPARγ agonists for the treatment of AD.

AB - Background: Peroxisome proliferator-activated receptor (PPAR) agonists reduce voluntary ethanol (EtOH) consumption in rat models and are promising therapeutics in the treatment for drug addictions. We studied the effects of different classes of PPAR agonists on chronic EtOH intake and preference in mice with a genetic predisposition for high alcohol consumption and then examined human genomewide association data for polymorphisms in PPAR genes in alcohol-dependent subjects. Methods: Two different behavioral tests were used to measure intake of 15% EtOH in C57BL/6J male mice: 24-hour 2-bottle choice and limited access (3-hour) 2-bottle choice, drinking in the dark. We measured the effects of pioglitazone (10 and 30 mg/kg), fenofibrate (50 and 150 mg/kg), GW0742 (10 mg/kg), tesaglitazar (1.5 mg/kg), and bezafibrate (25 and 75 mg/kg) on EtOH intake and preference. Fenofibric acid, the active metabolite of fenofibrate, was quantified in mouse plasma, liver, and brain by liquid chromatography tandem mass spectrometry. Data from a human genome-wide association study (GWAS) completed in the Collaborative Study on the Genetics of Alcoholism (COGA) were then used to analyze the association of single nucleotide polymorphisms (SNPs) in different PPAR genes (PPARA, PPARD, PPARG, and PPARGC1A) with 2 phenotypes: DSM-IV alcohol dependence (AD) and the DSM-IV criterion of withdrawal. Results: Activation of 2 isoforms of PPARs, α and γ, reduced EtOH intake and preference in the 2 different consumption tests in mice. However, a selective PPARδ agonist or a pan agonist for all 3 PPAR isoforms did not decrease EtOH consumption. Fenofibric acid, the active metabolite of the PPARα agonist fenofibrate, was detected in liver, plasma, and brain after 1 or 8 days of oral treatment. The GWAS from COGA supported an association of SNPs in PPARA and PPARG with alcohol withdrawal and PPARGC1A with AD but found no association for PPARD with either phenotype. Conclusions: We provide convergent evidence using both mouse and human data for specific PPARs in alcohol action. Reduced EtOH intake in mice and the genetic association between AD or withdrawal in humans highlight the potential for repurposing FDA-approved PPARα or PPARγ agonists for the treatment of AD.

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KW - Genome-Wide Association Study

KW - Pioglitazone

KW - Tesag-litazar

KW - Two-Bottle Choice

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