Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes

Authors

  • Swati Joshi-Barve,

    1. Department of Internal Medicine, the University of Louisville Medical Center, Louisville, KY
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  • Shirish S. Barve,

    1. Department of Internal Medicine, the University of Louisville Medical Center, Louisville, KY
    2. Department of Pharmacology and Toxicology, the University of Louisville Medical Center, Louisville, KY
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  • Kiranmayi Amancherla,

    1. Department of Internal Medicine, the University of Louisville Medical Center, Louisville, KY
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  • Leila Gobejishvili,

    1. Department of Internal Medicine, the University of Louisville Medical Center, Louisville, KY
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  • Daniell Hill,

    1. Department of Internal Medicine, the University of Louisville Medical Center, Louisville, KY
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  • Matthew Cave,

    1. Department of Internal Medicine, the University of Louisville Medical Center, Louisville, KY
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  • Prachi Hote,

    1. Department of Internal Medicine, the University of Louisville Medical Center, Louisville, KY
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  • Craig J. McClain

    Corresponding author
    1. Department of Internal Medicine, the University of Louisville Medical Center, Louisville, KY
    2. Department of Pharmacology and Toxicology, the University of Louisville Medical Center, Louisville, KY
    3. Louisville Veterans Administration Medical Center, Louisville, KY
    • Pharmacology and Toxicology, University of Louisville Medical Center, 550 S Jackson Street, ACB 3rd Floor, Louisville, KY 40292
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    • fax: 502-852-8927


  • Potential conflict of interest: Nothing to report.

Abstract

Obesity and the metabolic syndrome are closely correlated with hepatic steatosis. Simple hepatic steatosis in nonalcoholic fatty liver disease can progress to nonalcoholic steatohepatitis (NASH), which can be a precursor to more serious liver diseases, such as cirrhosis and hepatocellular carcinoma. The pathogenic mechanisms underlying progression of steatosis to NASH remain unclear; however, inflammation, proinflammatory cytokines, and oxidative stress have been postulated to play key roles. We previously reported that patients with NASH have elevated serum levels of proinflammatory cytokines, such as interleukin-8 (IL-8), which are likely to contribute to hepatic injury. This study specifically examines the effect of hepatic steatosis on IL-8 production. We induced lipid accumulation in hepatocytes (HepG2, rat primary hepatocytes, and human primary hepatocytes) by exposing them to pathophysiologically relevant concentrations of palmitic acid to simulate the excessive influx of fatty acids into hepatocytes. Significant fat accumulation was documented morphologically by Oil Red O staining in cells exposed to palmitic acid, and it was accompanied by an increase in intracellular triglyceride levels. Importantly, palmitic acid was found to induce significantly elevated levels of biologically active neutrophil chemoattractant, IL-8, from steatotic hepatocytes. Incubation of the cells with palmitate led to increased IL-8 gene expression and secretion (both mRNA and protein) through mechanisms involving activation of nuclear factor kappaB (NF-κB) and c-Jun N-terminal kinase/activator protein-1. Conclusion: These data demonstrate for the first time that lipid accumulation in hepatocytes can stimulate IL-8 production, thereby potentially contributing to hepatic inflammation and consequent liver injury. (HEPATOLOGY 2007.)

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