PPARβ/δ agonist GW0742 mitigates acute liver damage induced by acetaminophen overdose in mice

Liver damage caused by acetaminophen (APAP) overdose remains a worldwide medical problem. New therapeutic medicines for APAP poisoning are needed as the efficacy of the only antidote, N-acetyl-cysteine (NAC), significantly decreases if administered after 8 h of APAP intake and massive APAP overdose remains to induce hepatotoxicity despite the timely administration of NAC. Peroxisome Proliferator-activated Receptor β/δ (PPARβ/δ) possesses versatile roles including regulation of lipid homeostasis and anti-inflammation in the liver. This study aimed to investigate the effects of GW0742, one specific PPARβ/δ agonist, on APAP-caused liver damage in mice. We found that GW0742 (40 mg/kg, i.p.) pretreatment completely blocked the increase of serum aminotransferase activities, hepatocyte necrosis, oxidative stress, and liver inflammation in mice exposed to 300 mg/kg APAP (i.p.). Mechanistically, GW0742 pretreatment significantly suppressed the M1 polarization of liver Kupffer cells and activation of NLRP3 inflammasome. Interestingly, GW0742 remained effective when administered 6 h after APAP exposure, although its efficacy was less pronounced than that administered 6 h before the APAP challenge. Notably, GW0742 exhibited a more profound effect than NAC evidenced by the lower serum alanine transaminase (ALT) level and the improved histopathological manifestation. Furthermore, exposure to APAP for 6 h had resulted in dramatic liver inflammation, while pretreatment with GW0742 prior to APAP exposure did not influence the increase in serum aminotransferase activity and oxidative stress at 2 h after APAP exposure. These results highlight that PPARβ/δ may be a promising therapeutic target for treating APAP-caused acute liver damage probably acting on liver macrophages.

Acetaminophen; GW0742; Inflammation; N-acetyl cysteine; Oxidative stress; PPARβ/δ.