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Retinol saturase coordinates liver metabolism by regulating ChREBP activity

Author

Listed:
  • Steffi Heidenreich

    (Center for Cardiovascular Research)

  • Nicole Witte

    (Center for Cardiovascular Research)

  • Pamela Weber

    (Center for Cardiovascular Research)

  • Isabel Goehring

    (Center for Cardiovascular Research)

  • Alexander Tolkachov

    (Center for Cardiovascular Research)

  • Christian Loeffelholz

    (German Institute of Human Nutrition Potsdam-Rehbruecke
    Friedrich Schiller University
    Jena University Hospital)

  • Stephanie Döcke

    (German Institute of Human Nutrition Potsdam-Rehbruecke)

  • Michael Bauer

    (Friedrich Schiller University
    Jena University Hospital)

  • Martin Stockmann

    (Visceral and Transplantation Surgery)

  • Andreas F. H. Pfeiffer

    (German Institute of Human Nutrition Potsdam-Rehbruecke
    Department of Endocrinology, Diabetes, and Nutrition)

  • Andreas L. Birkenfeld

    (TU Dresden, University Clinic Dresden
    King’s College London)

  • Matthias Pietzke

    (Berlin Institute of Medical Systems Biology/Max- Delbrück Center for Molecular Medicine)

  • Stefan Kempa

    (Berlin Institute of Medical Systems Biology/Max- Delbrück Center for Molecular Medicine)

  • Matthias Muenzner

    (Center for Cardiovascular Research)

  • Michael Schupp

    (Center for Cardiovascular Research)

Abstract

The liver integrates multiple metabolic pathways to warrant systemic energy homeostasis. An excessive lipogenic flux due to chronic dietary stimulation contributes to the development of hepatic steatosis, dyslipidemia and hyperglycemia. Here we show that the oxidoreductase retinol saturase (RetSat) is involved in the development of fatty liver. Hepatic RetSat expression correlates with steatosis and serum triglycerides (TGs) in humans. Liver-specific depletion of RetSat in dietary obese mice lowers hepatic and circulating TGs and normalizes hyperglycemia. Mechanistically, RetSat depletion reduces the activity of carbohydrate response element binding protein (ChREBP), a cellular hexose-phosphate sensor and inducer of lipogenesis. Defects upon RetSat depletion are rescued by ectopic expression of ChREBP but not by its putative enzymatic product 13,14-dihydroretinol, suggesting that RetSat affects hepatic glucose sensing independent of retinol conversion. Thus, RetSat is a critical regulator of liver metabolism functioning upstream of ChREBP. Pharmacological inhibition of liver RetSat may represent a therapeutic approach for steatosis.

Suggested Citation

  • Steffi Heidenreich & Nicole Witte & Pamela Weber & Isabel Goehring & Alexander Tolkachov & Christian Loeffelholz & Stephanie Döcke & Michael Bauer & Martin Stockmann & Andreas F. H. Pfeiffer & Andreas, 2017. "Retinol saturase coordinates liver metabolism by regulating ChREBP activity," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00430-w
    DOI: 10.1038/s41467-017-00430-w
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