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

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• 作者：Saurabh Chatterjee¹ ; ² ; ^{schatt@mailbox.sc.edu} ; Douglas Ganini² ; Erik J. Tokar³ ; Ashutosh Kumar² ; Suvarthi Das¹ ; Jean Corbett² ; Maria B. Kadiiska² ; Michael P. Waalkes³ ; Anna Mae Diehl⁴ ; Ronald P. Mason²
• 关键词：Adipocytokines ; Kupffer cell ; Oxidative stress ; Tyrosine nitration ; NADPH oxidase ; ob/ob mice
• 刊名：Journal of Hepatology
• 出版年：2013
• 出版时间：April, 2013
• 年：2013
• 卷：58
• 期：4
• 页码：778-784
• 全文大小：930 K

文摘

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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.