High fat diet induced hepatic steatosis and insulin resistance: Role of dysregulated ceramide metabolism

Authors

  • Lisa Longato,

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

    1. Departments of Medicine, Pathology and Neurology, Divisions of Gastroenterology and Neuropathology, and the Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
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  • Jack R. Wands,

    1. Departments of Medicine, Pathology and Neurology, Divisions of Gastroenterology and Neuropathology, and the Liver Research Center, 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. Departments of Medicine, Pathology and Neurology, Divisions of Gastroenterology and Neuropathology, and the Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
      Dr Suzanne M. de la Monte, Pierre Galletti Research Building, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI 02903, USA. Email: suzanne_delamonte_md@brown.edu
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Dr Suzanne M. de la Monte, Pierre Galletti Research Building, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI 02903, USA. Email: suzanne_delamonte_md@brown.edu

Abstract

Aim:  Non-alcoholic fatty liver disease (NAFLD) is an insulin resistance disease that can progress to cirrhosis and liver failure. We hypothesized that in NAFLD, insulin resistance dysregulates lipid metabolism, increasing production of cytotoxic lipids including ceramides, which exacerbate hepatic insulin resistance and injury.

Methods:  Long Evans rats were pair-fed low (LFD) or high (HFD) fat diets for 8 weeks. Livers were used to measure lipids, gene expression, insulin receptor binding, integrity of insulin signaling, and pro-inflammatory cytokines. In vitro experiments characterized effects of ceramides on Huh7 cell viability, mitochondrial function, and insulin signaling.

Results:  High fat diet feeding caused NAFLD with peripheral and hepatic insulin resistance, increased hepatic expression of pro-ceramide genes, sphingomyelinase activity, and lipid peroxidation, and increased serum ceramide. Ceramide treatment impaired Huh7 cell viability, mitochondrial function, and insulin signaling.

Conclusions:  Increased hepatic ceramide generation and release may mediate both hepatic and peripheral insulin resistance in NAFLD.

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