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.