Structural Correlates of PPAR Agonist Rescue of Experimental Chronic Alcohol-Induced Steatohepatitis.
Chronic alcoholic liver disease is associated with hepatic insulin resistance, inflammation, oxidative and ER stress, mitochondrial dysfunction, and DNA damage. Peroxisome-proliferator activated receptor (PPAR) agonists are insulin sensitizers that have anti-inflammatory/anti-oxidant effects. We previously showed that PPAR agonists can restore hepatic insulin responsiveness in chronic ethanol-fed rats with steatohepatitis. Herein, we furthered our investigations by characterizing the histological and ultrastructural changes mediated by PPAR agonist rescue of alcohol-induced steatohepatitis. Adult male Long Evans rats were pair fed with isocaloric liquid diets containing 0% or 37% ethanol (caloric) for 8 weeks. After 3 weeks on the diets, rats were treated with vehicle, or a PPAR-α, PPAR-δ, or PPAR-γ agonist twice weekly by i.p. injection. Ethanol-fed rats developed steatohepatitis with disordered hepatic chord architecture, mega-mitochondria, disruption of the RER, increased apoptosis, and increased 4-hydroxynonenal (HNE) and 3-nitrotyrosine (NTyr) immunoreactivity. PPAR-δ and PPAR-γ agonists reduced the severity of steatohepatitis, and restored the hepatic chord-like architectural, mitochondrial morphology, and RER organization, and the PPAR-δ agonist significantly reduced hepatic HNE. On the other hand, prominent RER tubule dilation, which could reflect ER stress, persisted in ethanol-exposed, PPAR-γ treated but not PPAR-δ treated livers. The PPAR-α agonist exacerbated both steatohepatitis and formation of mega-mitochondria, and it failed to restore RER architecture or lower biochemical indices of oxidative stress. In conclusion, improved hepatic insulin responsiveness and decreased inflammation resulting from PPAR-δ or PPAR-γ agonist treatments of alcohol-induced steatohepatitis are likely mediated by enhanced signaling through metabolic pathways with attendant reductions in ER stress, oxidative stress, and mitochondrial dysfunction.
Liver Research Center and Departments of Medicine, Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
Teresa
T
Ramirez
Liver Research Center and Departments of Medicine, Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
Ming
M
Tong
Liver Research Center and Departments of Medicine, Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
Carol A
CA
Ayala
Liver Research Center and Departments of Medicine, Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
Paul R
PR
Monfils
Liver Research Center and Departments of Medicine, Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
Paul N
PN
McMillan
Liver Research Center and Departments of Medicine, Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
Valerie
V
Zabala
Liver Research Center and Departments of Medicine, Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
Jack R
JR
Wands
Liver Research Center and Departments of Medicine, Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI, USA.
Suzanne M
SM
de la Monte
Alcoholic liver disease; ER stress; Electron microscopy; Experimental model; Histopathology; Insulin resistance; PPAR agonists; Steatohepatitis