Retinol saturase coordinates liver metabolism by regulating ChREBP activity

Steffi Heidenreich, Nicole Witte, Pamela Weber, Isabel Goehring, Alexander Tolkachov, Christian Loeffelholz, Stephanie Döcke, Michael Bauer, Martin Stockmann, Andreas F. H. Pfeiffer, Andreas L. Birkenfeld, Matthias Pietzke, Stefan Kempa, Matthias Muenzner and Michael Schupp ()
Additional contact information
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
Stephanie Döcke: German Institute of Human Nutrition Potsdam-Rehbruecke
Michael Bauer: Friedrich Schiller University
Martin Stockmann: Visceral and Transplantation Surgery
Andreas F. H. Pfeiffer: German Institute of Human Nutrition Potsdam-Rehbruecke
Andreas L. Birkenfeld: TU Dresden, University Clinic Dresden
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

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00430-w

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