Mechanisms of diabetes-induced resistance against hepatotoxicity in mice

The primary objective of this study was to examine the modulation of hepatotoxicity due to streptozotocin-induced Type 1 diabetes (DB) in a murine animal model. Thioacetamide (TA), acetaminophen (APAP), chloroform (CHCl3) and bromobenzene (BB) caused lower hepatotoxicity and mortality in DB mice compared to their non-DB counterparts. Detailed studies were conducted with TA and APAP in C57BL6 and Swiss Webster mice, respectively. Liver injury (plasma ALT, AST, histopathology) and liver tissue repair (S-phase pulse labeling, PCNA immunohistochemistry) were examined over a time course. Results from these studies revealed decreased bioactivation-based liver injury and earlier onset and higher compensatory liver tissue repair in the DB mice.; The hypothesis that lower bioactivation-mediated liver injury of APAP in DB mice is due to lower hepatic microsomal CYP2E1 and/or 1A2 was investigated. HPLC analysis of plasma and urine levels of APAP and metabolites revealed lower t_1/2 of APAP in the diabetic mice and no difference in APAP-glucuronide, a major metabolite in mice. Greater clearance of APAP appears to play a role in the diabetes-induced role against APAP hepatotoxicity.; The importance of timely cell division and tissue repair was underscored by inhibiting DNA synthesis using an antimitotic agent, colchicine (CLC). Antimitotic intervention well after the bioactivation mechanisms of APAP were completed significantly reduced the protection conferred by diabetes. The mechanistic role of PPAR-α activation in diabetes as a hepatoprotective mechanism against lethal APAP challenge was investigated. PPAR-α −/− mice made diabetic by streptozotocin were devoid of CYP4A induction, in contrast to wild-type (WT) DB phenotypes, which showed considerable CYP4A induction. On treatment with APAP, WT-DB mice showed only 30% mortality and 50% less liver injury measured by ALT and histopathology. In contrast, DB-PPAR-α−/− mice were not protected against APAP toxicity suggesting the importance of PPAR-α in diabetes-induced protection. S-phase DNA synthesis and PCNA histochemical staining after injury showed earlier and robust tissue repair in WT-DB mice, but not in the PPAR-α −/−DB mice. Using c-DNA microarrays, the expression of 588 genes at 12 h after APAP treatment in non-DB and DB, WT and PPAR-α −/− mice was analyzed. Hierarchical clustering (Cluster™) of genes revealed six groups of genes, with correlations among genes from similar functional families. Microarray data were confirmed via real-time PCR analysis of 15 genes. These findings suggest enhanced p38 MAPK/cyclin D1 signaling and heat shock protein induction in diabetes via PPAR-α activation in diabetes, as mechanisms underlying upregulated liver tissue repair and survival. (Abstract shortened by UMI.)...