Hepatic carboxylesterase 1 is essential for both normal and farnesoid X receptor-controlled lipid homeostasis

Authors

  • Jiesi Xu,

    1. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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    • These authors contributed equally to this work.

  • Yuanyuan Li,

    1. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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    • These authors contributed equally to this work.

  • Wei-Dong Chen,

    1. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
    2. Key Laboratory of Receptor-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, China
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    • These authors contributed equally to this work.

  • Yang Xu,

    1. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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    • These authors contributed equally to this work.

  • Liya Yin,

    1. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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  • Xuemei Ge,

    1. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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  • Kavita Jadhav,

    1. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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  • Luciano Adorini,

    1. Intercept Pharmaceuticals, New York, NY, USA
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  • Yanqiao Zhang

    Corresponding author
    1. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
    • Address reprint requests to: Dr. Yanqiao Zhang, Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272. E-mail: yzhang@neomed.edu; fax: 330-325-5912.

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  • See Editorial on Page 1665

    Potential conflict of interest: Dr. Adorini is employed by and owns stock in Intercept.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in regulating both normal and FXR-controlled lipid homeostasis. Overexpression of hepatic CES1 lowered hepatic TG and plasma glucose levels in both wild-type and diabetic mice. In contrast, knockdown of hepatic CES1 increased hepatic TG and plasma cholesterol levels. These effects likely resulted from the TG hydrolase activity of CES1, with subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Activation of FXR induced hepatic CES1, and reduced the levels of hepatic and plasma TG as well as plasma cholesterol in a CES1-dependent manner. Conclusion: Hepatic CES1 plays a critical role in regulating both lipid and carbohydrate metabolism and FXR-controlled lipid homeostasis. (Hepatology 2014;59:1761–1771)

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