Skip to main content
Journal cover image

Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis.

Publication ,  Journal Article
Chatterjee, S; Ganini, D; Tokar, EJ; Kumar, A; Das, S; Corbett, J; Kadiiska, MB; Waalkes, MP; Diehl, AM; Mason, RP
Published in: J Hepatol
April 2013

BACKGROUND & AIMS: Progression from steatosis to steatohepatitic lesions is hypothesized to require a second hit. These lesions have been associated with increased oxidative stress, often ascribed to high levels of leptin and other proinflammatory mediators. Here we have examined the role of leptin in inducing oxidative stress and Kupffer cell activation in CCl4-mediated steatohepatitic lesions of obese mice. METHODS: Male C57BL/6 mice fed with a high-fat diet (60%kcal) at 16 weeks were administered CCl₄ to induce steatohepatitic lesions. Approaches included use of immuno-spin trapping for measuring free radical stress, gene-deficient mice for leptin, p47 phox, iNOS and adoptive transfer of leptin primed macrophages in vivo. RESULTS: Diet-induced obese (DIO) mice, treated with CCl4 increased serum leptin levels. Oxidative stress was significantly elevated in the DIO mouse liver, but not in ob/ob mice, or in DIO mice treated with leptin antibody. In ob/ob mice, leptin supplementation restored markers of free radical generation. Markers of free radical formation were significantly decreased by the peroxynitrite decomposition catalyst FeTPPS, the iNOS inhibitor 1400W, the NADPH oxidase inhibitor apocynin, or in iNOS or p47 phox-deficient mice. These results correlated with the decreased expression of TNF-alpha and MCP-1. Kupffer cell depletion eliminated oxidative stress and inflammation, whereas in macrophage-depleted mice, the adoptive transfer of leptin-primed macrophages significantly restored inflammation. CONCLUSIONS: These results, for the first time, suggest that leptin action in macrophages of the steatotic liver, through induction of iNOS and NADPH oxidase, causes peroxynitrite-mediated oxidative stress thus activating Kupffer cells.

Duke Scholars

Published In

J Hepatol

DOI

EISSN

1600-0641

Publication Date

April 2013

Volume

58

Issue

4

Start / End Page

778 / 784

Location

Netherlands

Related Subject Headings

  • Peroxynitrous Acid
  • Oxidative Stress
  • Obesity
  • Non-alcoholic Fatty Liver Disease
  • Nitric Oxide Synthase Type II
  • NADPH Oxidases
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Leptin
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Chatterjee, S., Ganini, D., Tokar, E. J., Kumar, A., Das, S., Corbett, J., … Mason, R. P. (2013). Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis. J Hepatol, 58(4), 778–784. https://doi.org/10.1016/j.jhep.2012.11.035
Chatterjee, Saurabh, Douglas Ganini, Erik J. Tokar, Ashutosh Kumar, Suvarthi Das, Jean Corbett, Maria B. Kadiiska, Michael P. Waalkes, Anna Mae Diehl, and Ronald P. Mason. “Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis.J Hepatol 58, no. 4 (April 2013): 778–84. https://doi.org/10.1016/j.jhep.2012.11.035.
Chatterjee S, Ganini D, Tokar EJ, Kumar A, Das S, Corbett J, et al. Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis. J Hepatol. 2013 Apr;58(4):778–84.
Chatterjee, Saurabh, et al. “Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis.J Hepatol, vol. 58, no. 4, Apr. 2013, pp. 778–84. Pubmed, doi:10.1016/j.jhep.2012.11.035.
Chatterjee S, Ganini D, Tokar EJ, Kumar A, Das S, Corbett J, Kadiiska MB, Waalkes MP, Diehl AM, Mason RP. Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis. J Hepatol. 2013 Apr;58(4):778–784.
Journal cover image

Published In

J Hepatol

DOI

EISSN

1600-0641

Publication Date

April 2013

Volume

58

Issue

4

Start / End Page

778 / 784

Location

Netherlands

Related Subject Headings

  • Peroxynitrous Acid
  • Oxidative Stress
  • Obesity
  • Non-alcoholic Fatty Liver Disease
  • Nitric Oxide Synthase Type II
  • NADPH Oxidases
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Leptin