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

Am J Physiol Gastrointest Liver Physiol. 2001 Aug;281(2):G382-92. doi: 10.1152/ajpgi.2001.281.2.G382.


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-kappaB (NF-kappaB) 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 kappa-B are activated; NF-kappaB activity is induced, and NF-kappaB-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 kappa-B, enhanced activation of NF-kappaB, and greater induction of NF-kappaB-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-alpha, these findings suggest that fatty livers are sensitive to LPS damage because of vulnerability to necrosis, rather than because of apoptosis.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Apoptosis
  • Caspase 3
  • Caspase Inhibitors*
  • Cells, Cultured
  • Enzyme Activation
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Lipopolysaccharides / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Minor Histocompatibility Antigens
  • NF-kappa B / metabolism*
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase Type II
  • Protein Biosynthesis
  • Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • RNA, Messenger / biosynthesis
  • Tumor Necrosis Factor-alpha / pharmacology
  • bcl-X Protein


  • BCL2-related protein A1
  • Bcl2l1 protein, mouse
  • Caspase Inhibitors
  • Lipopolysaccharides
  • Minor Histocompatibility Antigens
  • NF-kappa B
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • bcl-X Protein
  • Adenosine Triphosphate
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Casp3 protein, mouse
  • Caspase 3