Therapeutic reversal of chronic alcohol-related steatohepatitis with the ceramide inhibitor myriocin

Authors

  • Ming Tong,

    1. Liver Research Center, Division of Gastroenterology, Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
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    • Ming Tong and Lisa Longato contributed equally.
  • Lisa Longato,

    1. Liver Research Center, Division of Gastroenterology, Brown University, Providence, Providence, RI, USA
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    • Ming Tong and Lisa Longato contributed equally.
  • Teresa Ramirez,

    1. Liver Research Center, Division of Gastroenterology, Brown University, Providence, Providence, RI, USA
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  • Valerie Zabala,

    1. Liver Research Center, Division of Gastroenterology, Brown University, Providence, Providence, RI, USA
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  • Jack R. Wands,

    1. Liver Research Center, Division of Gastroenterology, Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
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  • Suzanne M. de la Monte

    Corresponding author
    1. Liver Research Center, Divisions of Gastroenterology and Neuropathology, and Departments of Medicine, Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
    • Correspondence:

      Dr. Suzanne M. de la Monte

      Rhode Island Hospital and the Warren Alpert Medical School of Brown University

      Pierre Galletti Research Building

      55 Claverick Street

      Room 419

      Providence

      RI 02903

      USA

      Tel.: 401 444 7364

      Fax: 401 444 2939

      E-mail: suzanne_delamonte_md@brown.edu

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Summary

Alcohol-related liver disease (ALD) is associated with steatohepatitis and insulin resistance. Insulin resistance impairs growth and disrupts lipid metabolism in hepatocytes. Dysregulated lipid metabolism promotes ceramide accumulation and oxidative stress, leading to lipotoxic states that activate endoplasmic reticulum (ER) stress pathways and worsen inflammation and insulin resistance. In a rat model of chronic alcohol feeding, we characterized the effects of a ceramide inhibitor, myriocin, on the histopathological and ultrastructural features of steatohepatitis, and the biochemical and molecular indices of hepatic steatosis, insulin resistance and ER stress. Myriocin reduced the severity of alcohol-related steatohepatitis including the abundance and sizes of lipid droplets and mitochondria, inflammation and architectural disruption of the ER. In addition, myriocin-mediated reductions in hepatic lipid and ceramide levels were associated with constitutive enhancement of insulin signalling through the insulin receptor and IRS-2, reduced hepatic oxidative stress and modulation of ER stress signalling mechanisms. In conclusion, ceramide accumulation in liver mediates tissue injury, insulin resistance and lipotoxicity in ALD. Reducing hepatic ceramide levels can help restore the structural and functional integrity of the liver in chronic ALD due to amelioration of insulin resistance and ER stress. However, additional measures are needed to protect the liver from alcohol-induced necroinflammatory responses vis-à-vis continued alcohol abuse.

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