PPARdelta agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair.
OBJECTIVE
Chronic ethanol exposure impairs liver regeneration due to inhibition of insulin signaling and oxidative injury. PPAR agonists function as insulin sensitizers and anti-inflammatory agents. We investigated whether treatment with a PPARdelta agonist could restore hepatic insulin sensitivity, survival signaling, and regenerative responses vis-a-vis chronic ethanol feeding.


METHODS
Adult rats were fed isocaloric liquid diets containing 0% or 37% ethanol, and administered a PPARdelta agonist by i.p. injection. We used liver tissue to examine histopathology, gene expression, oxidative stress, insulin signaling, and regenerative responses to 2/3 hepatectomy.


RESULTS
Chronic ethanol feeding caused insulin resistance, increased oxidative stress, lipid peroxidation, DNA damage, and hepatocellular injury in liver. These effects were associated with reduced insulin receptor binding and affinity, impaired survival signaling through PI3K/Akt/GSK3beta, and reduced expression of insulin responsive genes mediating energy metabolism and tissue remodeling. PPARdelta agonist treatment reduced ethanol-mediated hepatic injury, oxidative stress, lipid peroxidation, and insulin resistance, increased signaling through PI3K/Akt/GSK3beta, and enhanced the regenerative response to partial hepatectomy.


CONCLUSIONS
PPARdelta agonist administration may attenuate the severity of chronic ethanol-induced liver injury and ethanol's adverse effects on the hepatic repair by restoring insulin responsiveness, even in the context of continued high-level ethanol consumption.
Pang
Maoyin
M
Liver Research Center and Department of Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, 55 Claverick Street, Providence, RI 02903, USA.
de la Monte
Suzanne M
SM
Longato
Lisa
L
Tong
Ming
M
He
Jiman
J
Chaudhry
Rajeeve
R
Duan
Kevin
K
Ouh
Jiyun
J
Wands
Jack R
JR
D000818:Animals; D004249:DNA Damage; D000431:Ethanol / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D047494:PPAR delta / Q000819:agonists*; D010642:Phenoxyacetates / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; D007328:Insulin; D047494:PPAR delta; D010642:Phenoxyacetates; D000431:Ethanol; D017526:Receptor, IGF Type 1