Fatty liver vulnerability to endotoxin-induced damage despite NF-kappa B induction and inhibited caspase 3 activation

Fatty livers are sensitive to lipopolysaccharide (LPS) damage. This study t ests the hypothesis that this vulnerability occurs because protective, anti apoptotic mechanisms are not upregulated appropriately. Genetically obese, leptin-deficient ob/ob mice, a model for nonalcoholic fatty liver disease, and their lean litter mates were treated with a small dose of LPS. General measures of liver injury, early (i.e., cytochrome c release) and late (i.e. , activation of caspase 3) events that occur during hepatocyte apoptosis, a nd various aspects of the signal transduction pathways that induce nuclear factor-kappaB (NF-kappaB) and several of its antiapoptotic transcriptional targets (e.g., inducible nitric oxide synthase, bfl-1, and bcl-xL) were com pared. Within 0.5-6 h after LPS exposure, cytochrome c begins to accumulate in the cytosol of normal livers, and procaspase 3 cleavage increases. Coin cident with these events, kinases (e.g., AKT and Erk-1 and -2) that result in the degradation of inhibitor kappa -B are activated; NF-kappaB activity is induced, and NF-kappaB-regulated gene products accumulate. Throughout th is period, there is negligible histological evidence of liver damage, and s erum alanine aminotransferase values barely increase over baseline values. Although ob/ob livers have significant histological liver injury and 11-fol d greater serum alanine aminotransferase values than those of lean mice by 6 h post-LPS, they exhibit greater activation of AKT and Erk, more profound reductions in inhibitor kappa -B, enhanced activation of NF-kappaB, and gr eater induction of NF-kappaB-regulated genes. Consistent with this heighten ed antiapoptotic response, increases in cytochrome c and procaspase 3 cleav age products are inhibited. Together with evidence that ob/ob hepatocytes h ave a reduced ATP content and undergo increased lysis after in vitro exposu re to tumor necrosis factor-alpha, these findings suggest that fatty livers are sensitive to LPS damage because of vulnerability to necrosis, rather t han because of apoptosis.