Activation of PPAR-alpha in streptozotocin-induced diabetes is essential for resistance against acetaminophen toxicity.

Diabetic (DB) mice exhibit significant resistance to hepatotoxicants. The role of peroxisome proliferator receptor (PPAR)-alpha activation in diabetes, in protection against lethal acetaminophen (APAP) challenge, was investigated. Upon treatment with APAP (600 mg/kg, i.p., a LD100 dose in wild-type [WT] non-DB mice), WT-DB mice showed only 30% mortality and 40% less liver injury as measured by alanine aminotransferase and histopathology. In contrast, diabetes in PPAR knockout (PPAR-alpha-/-) mice failed to protect against APAP toxicity, suggesting the importance of PPAR-alpha in diabetes-induced protection. S-phase DNA synthesis and PCNA immunohistochemical staining after injury showed early and robust tissue repair in WT-DB mice, but not in the PPAR-alpha-/--DB mice. Microarray analyses were performed on livers from non-DB and DB (WT and PPAR-alpha-/-) mice at 0 and 12 h after APAP. Microarray data were confirmed via real-time polymerase chain reaction analysis of several genes, including stress response, immediate early genes, DNA damage, heat shock proteins, and cell cycle regulators, followed by Western analyses of selected proteins. Gel shift assays revealed higher activation of nuclear factor-kappaB in WT-DB mice after APAP treatment. These findings suggest PPAR-alpha activation as a hepatoprotective adaptive response mediating protection against APAP in diabetes.