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B induction and inhibited caspase 3 activation
Department of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205
Fatty livers
are sensitive to lipopolysaccharide (LPS) damage. This study tests the
hypothesis that this vulnerability occurs because protective,
antiapoptotic 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, and various aspects of the signal transduction
pathways that induce nuclear factor-
B (NF-B) and several of its
antiapoptotic transcriptional targets (e.g., inducible nitric oxide
synthase, bfl-1, and bcl-xL) were compared. Within 0.5-6 h after
LPS exposure, cytochrome c begins to accumulate in the
cytosol of normal livers, and procaspase 3 cleavage increases.
Coincident with these events, kinases (e.g., AKT and Erk-1 and -2) that
result in the degradation of inhibitor -B are activated; NF-B
activity is induced, and NF-B-regulated gene products accumulate.
Throughout this period, there is negligible histological evidence of
liver damage, and serum alanine aminotransferase values barely increase
over baseline values. Although ob/ob livers have significant
histological liver injury and 11-fold 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 -B, enhanced activation of NF-B, and
greater induction of NF-B-regulated genes. Consistent with this
heightened antiapoptotic response, increases in cytochrome c and procaspase 3 cleavage products are inhibited. Together
with evidence that ob/ob hepatocytes have a reduced ATP content and undergo increased lysis after in vitro exposure to tumor necrosis factor-
, these findings suggest that fatty livers are sensitive to
LPS damage because of vulnerability to necrosis, rather than because of apoptosis.
nuclear factor-B; obesity; nonalcoholic fatty liver
disease
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