Ischemia-reperfusion injury (IRI) remains a frequent complication in surgery, especially in case of steatotic livers that present decreased tolerance towards IRI. Apart from its major role in metabolism, activation of
peroxisome proliferator-activated receptor α (PPARα) has been related with positive effects on IRI. In addition, the deacetylase
enzyme sirtuin 1 (
SIRT1) has recently emerged as a promising target for preventing IRI, through its interaction with stress-related mechanisms, such as endoplasmic reticulum stress (ERS). Taking this into account, this study aims to explore whether PPARα agonist
WY-14643 could protect steatotic livers against IRI through
sirtuins and ERS signaling pathway. Obese Zucker rats were pretreated or not pretreated with
WY-14643 (10 mg/kg intravenously) and then submitted to partial (70%) hepatic
ischemia (1 hour) followed by 24 hours of reperfusion. Liver injury (ALT levels), lipid peroxidation (MDA),
SIRT1 activity, and the
protein expression of
SIRT1 and
SIRT3 and ERS parameters (IRE1α, peIF2,
caspase 12, and CHOP) were evaluated. Treatment with
WY-14643 reduced liver injury in fatty livers, enhanced
SIRT1 activity, and prevented ERS. Together, our results indicated that PPARα agonist
WY-14643 may exert its protective effect in fatty livers, at least in part, via
SIRT1 induction and ERS prevention.