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Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation.

Publication ,  Journal Article
Koteish, A; Yang, S; Lin, H; Huang, X; Diehl, AM
Published in: J Biol Chem
April 12, 2002

Although ethanol is known to sensitize hepatocytes to tumor necrosis factor (TNF) lethality, the mechanisms involved remain controversial. Recently, others have shown that adding TNFalpha to cultures of ethanol-pretreated hepatocytes provokes the mitochondrial permeability transition, cytochrome c release, procaspase 3 activation, and apoptosis. Although this demonstrates that ethanol can sensitize hepatocytes to TNF-mediated apoptosis, the hepatic inflammation and ballooning hepatocyte degeneration that typify alcohol-induced liver injury suggest that other mechanisms might predominate in vivo. To evaluate this possibility, acute responses to lipopolysaccharide (LPS), a potent inducer of TNFalpha, were compared in mice that had been fed either an ethanol-containing or control diet for 5 weeks. Despite enhanced induction of cytokines such as interleukin (IL)-10, IL-15, and IL-6 that protect hepatocytes from apoptosis, ethanol-fed mice exhibited a 4-5-fold increase in serum alanine aminotransferase after LPS, confirming increased liver injury. Six h post-LPS histology also differed notably in the two groups, with control livers demonstrating only scattered apoptotic hepatocytes, whereas ethanol-exposed livers had large foci of ballooned hepatocytes, inflammation, and scattered hemorrhage. No caspase 3 activity was noted during the initial 6 h after LPS in ethanol-fed mice, but this tripled by 1.5 h after LPS in controls. Procaspase 8 cleavage and activity of the apoptosis-associated kinase, Jun N-terminal kinase, were also greater in controls. In contrast, ethanol exposure did not inhibit activation of cytoprotective mitogen-activated protein kinases and AKT or attenuate induction of the anti-apoptotic factors NF-kappaB and inducible nitric oxide synthase. Consistent with these responses, neither cytochrome c release, an early apoptotic response, nor hepatic oligonucleosomal DNA fragmentation, the ultimate consequence of apoptosis, was increased by ethanol. Thus, ethanol exacerbates TNF-related hepatotoxicity in vivo without enhancing caspase 3-dependent apoptosis.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

April 12, 2002

Volume

277

Issue

15

Start / End Page

13037 / 13044

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase
  • NF-kappa B
  • Mitogen-Activated Protein Kinases
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Liver
  • Lipopolysaccharides
 

Citation

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Koteish, A., Yang, S., Lin, H., Huang, X., & Diehl, A. M. (2002). Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation. J Biol Chem, 277(15), 13037–13044. https://doi.org/10.1074/jbc.M101632200
Koteish, Ayman, ShiQi Yang, HuiZhi Lin, Xiawen Huang, and Anna Mae Diehl. “Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation.J Biol Chem 277, no. 15 (April 12, 2002): 13037–44. https://doi.org/10.1074/jbc.M101632200.
Koteish A, Yang S, Lin H, Huang X, Diehl AM. Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation. J Biol Chem. 2002 Apr 12;277(15):13037–44.
Koteish, Ayman, et al. “Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation.J Biol Chem, vol. 277, no. 15, Apr. 2002, pp. 13037–44. Pubmed, doi:10.1074/jbc.M101632200.
Koteish A, Yang S, Lin H, Huang X, Diehl AM. Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation. J Biol Chem. 2002 Apr 12;277(15):13037–13044.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

April 12, 2002

Volume

277

Issue

15

Start / End Page

13037 / 13044

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase
  • NF-kappa B
  • Mitogen-Activated Protein Kinases
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Liver
  • Lipopolysaccharides