Peroxisome proliferator-activated receptors α and γ are linked with alcohol consumption in mice and withdrawal and dependence in humans.

paper Primary Public

Authors: Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy; Ferguson, Laura B; Schoenhard, Grant L; Goate, Alison M; Edenberg, Howard J; Wetherill, Leah; Hesselbrock, Victor; Foroud, Tatiana; Harris, R Adron
Year: 2015
Journal: Alcoholism, clinical and experimental research
PMID: 25516156
DOI: 10.1111/acer.12610
PMCID: PMC4308472

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.

Figure 1

Effects of PPAR agonists on ethanol intake after the first 6 hours in the 24-hour two-bottle choice test in C57BL/6J male miceAfter at least 3 weeks of 15% ethanol consumption and after stable intake was reached, ethanol (EtOH) consumption was measured (g/kg/6 hours) after 2 days of saline administration (day 2 in graph) and mice were grouped to provide similar levels of ethanol intake and preference. Beginning on day 3, saline or drug was administered and intake averaged over 2-day periods using different bottle positions (see Methods for details). A. Pioglitazone (n=13) B. Fenofibrate (n=6) C. GW0742 (n=6) D. Tesaglitazar (n=6) E. Bezafibrate (n=6). Data were analyzed by two-way repeated measures ANOVA followed by Bonferroni’s test for multiple comparisons. *p<0.05; **p<0.01; ***p<0.001 compared to control.

Figure 2

Effects of PPAR agonists on ethanol intake during limited access (3-hour) two-bottle choice Drinking in the Dark test in C57BL/6J male miceAfter at least 3 weeks of 15% ethanol consumption and after stable intake was reached, ethanol (EtOH) consumption was measured (g/kg/3 hours) after 2 days of saline administration (day 2 in graph) and mice were grouped to provide similar levels of ethanol intake and preference. Beginning on day 3, saline or drug was administered and intake averaged over 2-day periods using different bottle positions (see Methods for details). A. Pioglitazone B. Fenofibrate C. GW0742 D. Tesaglitazar E. Bezafibrate. Data were analyzed by Student's t-test or two-way repeated measures ANOVA followed by Bonferroni’s test for multiple comparisons. *p<0.05; **p<0.01; ***p<0.001 compared to control. (n=6 for all groups)

Figure 3

Association results from the Collaborative Study on the Genetics of Alcoholism (COGA)A. PPARA and withdrawal B. PPARG and withdrawal C. PPARGC1A and AD. Y-axis denotes the –log10 (p-value) for association. X-axis is the physical position on the chromosome (Mb). The most significantly associated SNP is denoted with a purple symbol, and the SNP name is shown below the color scale. The extent of linkage disequilibrium (LD, as measured by r2) between each SNP and the most significantly associated SNP with the lowest p-value within the gene is indicated by the color scale. Larger values of r2 indicate greater LD. Association results with genotyped SNPs are shown as a circle while association results with imputed SNPs are shown as a square.

#	Section	Preview
20	RESULTS	In a ‘binge’ model of limited access to ethanol, pioglitazone had no effect (Figure 2 A;…
21	RESULTS	We collected plasma, liver, and brain samples from mice treated for 1 or 8 days with 150 mg/kg of…
22	RESULTS	We sought to link our novel results in mice to human alcoholism using data from COGA. We selected…
23	RESULTS	studies of PPARG to include the gene for its transcriptional coactivator, PPARGC1A. We tested 46…
24	DISCUSSION	Our results show that activation of PPARα and PPARγ (but not PPARδ) reduces ethanol intake and…
25	DISCUSSION	The ability of PPAR ligands to trans-repress or inhibit the activity of transcription factors like…
26	DISCUSSION	of both innate and adaptive immunity (Boersma and Meffert, 2008), and NF-κB and its signaling…
27	DISCUSSION	induced changes in the expression of immune-related genes in the liver but did not produce prominent…
28	DISCUSSION	The selective PPAR effects that we observed in mice are supported by human genomic data, suggesting…
29	DISCUSSION	PPAR agonists may have limited ability to reach the brain in rodents (Dasgupta et al., 2007; Weil et…
30	DISCUSSION	PPARγ antagonist injected into the lateral cerebroventricle, indicating a direct action of PPAR…
31	DISCUSSION	Furthermore, there are examples of PPAR activation affecting brain function via their systemic…
32	DISCUSSION	Some of the behavioral effects that we observed might be attributed to the systemic effects of PPAR…
33	DISCUSSION	PPAR agonists with fewer side effects are being sought, and PPARα agonists are widely used and…
34	DISCUSSION	Overall, PPAR agonists are beneficial for treating several key problems of AD: i) excessive…
35	DISCUSSION	An overall similar approach recently showed that SNPs of FKBP5 were associated with alcohol…

Name	Type
24-hour two-bottle choice test local	phenotype
acamprosate	drug
aging	phenotype
alcohol	phenotype
alcohol dehydrogenase	gene
alcohol dependence	phenotype
alcohol-dependent rats	cohort
Alcoholic proband	cohort
alcoholism	phenotype
alcohol-preferring rats	cohort
alcohol-related phenotypes	phenotype
Alcohol Use Disorder	phenotype
alcohol withdrawal	phenotype
ALDH2	gene
Alzheimer's disease	phenotype
Animal Resources Center local	cohort
baseline drinking local	phenotype
basolateral amygdala	anatomy
bezafibrate local	drug
Bezafibrate local	drug
body weight	phenotype
brain	anatomy
C57BL/6J	cohort
C57BL/6J male mice local	cohort
caffeic acid phenylethyl ester local	drug
chronic ethanol exposure	phenotype
CNS	anatomy
cognition	phenotype
Collaborative Study on the Genetics of Alcoholism (COGA)	cohort
control group	cohort
disulfiram	drug
dopamine release	drug
drug	drug
drug dependence	phenotype
Drug group local	cohort
drugs	drug
ethanol consumption	phenotype
ethanol naive local	phenotype
ethanol preference	phenotype
European ancestry	cohort
excessive alcohol consumption	phenotype
fenofibrate	drug
Fkbp5	gene
Fkbp5 knockout mice local	cohort
FKBP5 SNPs local	variant
gabapentin	drug
Gemfibrozil local	drug
GW0742 local	drug
High-alcohol-preferring mice local	cohort
high-ethanol-consuming mice local	cohort
high-fat diet	drug
human alcoholics	phenotype
Human cohort	cohort
humans	cohort
Huntington's disease	phenotype
hyperactivity	phenotype
IKBKB	gene
imputed SNPs	variant
Ischemic brain injury local	phenotype
Jackson Laboratories local	cohort
lateral cerebroventricle local	anatomy
Lateral cerebroventricle local	anatomy
limited access drinking test local	phenotype
liver	anatomy
liver injury	phenotype
memory	phenotype
Memory retention local	phenotype
mice	cohort
Motivation deficits local	phenotype
motor activity	phenotype
mouse brain	anatomy
Mouse models of excessive alcohol consumption local	cohort
MPTP	drug
naltrexone	drug
neurodegeneration	phenotype
neurodegenerative disease	phenotype
neurodegenerative diseases	phenotype
neurological disorders	phenotype
neuroprotection	phenotype
NFKB1	gene
NF-κB	gene
NF-κB inhibitors local	drug
nicotine use	phenotype
Oleoylethanolamide	drug
Parkinson's disease	phenotype
PGC-1α local	drug
pioglitazone	drug
plasma local	cohort
post-mortem brain local	anatomy
PPAR	gene
PPARA	gene
PPARA agonist local	drug
PPAR agonist local	drug
PPAR agonists local	drug
PPARD	gene
PPARG	gene
PPARG agonist local	drug
PPARGC1A	gene
PPARs local	drug
PPARα	gene
PPARγ	gene
PPARγ antagonist local	drug
prefrontal cortex	anatomy
rats	cohort
Relapse-dependent symptoms local	phenotype
rosiglitazone	drug
RXR	gene
saline	drug
schizophrenia	phenotype
selective PPARG antagonist local	drug
Selective PPARγ antagonist local	drug
SNP	cohort
stress-induced reinstatement	phenotype
tesaglitazar	drug
tolbutamide local	drug
Tween-80 local	drug
Two-bottle choice test local	phenotype
unaffected	phenotype
University of Texas at Austin local	cohort
voluntary alcohol consumption	phenotype
warfarin	drug
water	drug
water intake	phenotype
withdrawal	phenotype
Withdrawal Criterion (DSM-IV) local	phenotype

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Testing the PPAR hypothesis of tobacco use disorder in humans: A randomized trial of the impact of gemfibrozil (a partial PPARα agonist) in smokers.	Gendy MNS et al.	—	2018	→
Transcriptional Regulators as Targets for Alcohol Pharmacotherapies.	Savarese AM et al.	—	2018	→
Fenofibrate Administration Reduces Alcohol and Saccharin Intake in Rats: Possible Effects at Peripheral and Central Levels.	Rivera-Meza M et al.	—	2017	→
Genetic studies of alcohol dependence in the context of the addiction cycle.	Reilly MT et al.	—	2017	→
Glial and neuroinflammatory targets for treating substance use disorders.	Bachtell RK et al.	—	2017	→
Midkine in the mouse ventral tegmental area limits ethanol intake and Ccl2 gene expression.	Chen H et al.	—	2017	→
Peripheral immune system suppression in early abstinent alcohol-dependent individuals: Links to stress and cue-related craving.	Fox HC et al.	—	2017	→
Promising pharmacogenetic targets for treating alcohol use disorder: evidence from preclinical models.	Rinker JA et al.	—	2017	→
Protection against alcohol-induced neuronal and cognitive damage by the PPARγ receptor agonist pioglitazone.	Cippitelli A et al.	—	2017	→
Two novel candidate genes identified in adults from the Newfoundland population with addictive tendencies towards food.	Pedram P et al.	—	2017	→
Chronic Moderate Alcohol Intakes Accelerate SR-B1 Mediated Reverse Cholesterol Transport.	Li M et al.	—	2016	→
Emerging targets for addiction neuropharmacology: From mechanisms to therapeutics.	Ubaldi M et al.	—	2016	→
Ethanol-induced changes in poly (ADP ribose) polymerase and neuronal developmental gene expression.	Gavin DP et al.	—	2016	→
Evaluation of TLR4 Inhibitor, T5342126, in Modulation of Ethanol-Drinking Behavior in Alcohol-Dependent Mice.	Bajo M et al.	—	2016	→
Gene Expression Changes in Glutamate and GABA-A Receptors, Neuropeptides, Ion Channels, and Cholesterol Synthesis in the Periaqueductal Gray Following Binge-Like Alcohol Drinking by Adolescent Alcohol-Preferring (P) Rats.	McClintick JN et al.	—	2016	→
Genes and Alcohol Consumption: Studies with Mutant Mice.	Mayfield J et al.	—	2016	→
Guduchi Sawras (Tinospora cordifolia): An Ayurvedic drug treatment modulates the impaired lipid metabolism in alcoholics through dopaminergic neurotransmission and anti-oxidant defense system.	Shirolkar A et al.	—	2016	→
Inflammatory responses to alcohol in the CNS: nuclear receptors as potential therapeutics for alcohol-induced neuropathologies.	Kane CJ et al.	—	2016	→
Peroxisome Proliferator-Activated Receptor-γ Agonists: Potential Therapeutics for Neuropathology Associated with Fetal Alcohol Spectrum Disorders.	Drew PD et al.	—	2016	→
PPAR Agonists: II. Fenofibrate and Tesaglitazar Alter Behaviors Related to Voluntary Alcohol Consumption.	Blednov YA et al.	—	2016	→
PPAR Agonists: I. Role of Receptor Subunits in Alcohol Consumption in Male and Female Mice.	Blednov YA et al.	—	2016	→
Preclinical Medication Development: New Targets and New Drugs.	Kasten CR et al.	—	2016	→
Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction.	Mayfield J et al.	—	2015	→
Commonalities and Distinctions Among Mechanisms of Addiction to Alcohol and Other Drugs.	Ozburn AR et al.	—	2015	→
PPARα Agonists Reduce Alcohol Drinking: Do They Act in the Brain or in the Liver?	Karahanian E et al.	—	2015	→
Neuroimmune pathways in alcohol consumption: evidence from behavioral and genetic studies in rodents and humans.	Robinson G et al.	—	2014	→