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Nat Commun. 2017 Aug 30;8(1):384. doi: 10.1038/s41467-017-00430-w.

Retinol saturase coordinates liver metabolism by regulating ChREBP activity.

Author information

1
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pharmacology, Center for Cardiovascular Research, Berlin, 10115, Germany.
2
Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, 14558, Germany.
3
Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Friedrich Schiller University, Jena, 07747, Germany.
4
Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena, 07747, Germany.
5
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of General, Visceral and Transplantation Surgery, Virchow Campus, Berlin, 13353, Germany.
6
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology, Diabetes, and Nutrition, Berlin, 10117, Germany.
7
Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, University Clinic Dresden, Dresden, 01307, Germany.
8
Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London, SE1 8WA, UK.
9
Integrative Metabolomics and Proteomics, Berlin Institute of Medical Systems Biology/Max- Delbrück Center for Molecular Medicine, Berlin, 13125, Germany.
10
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pharmacology, Center for Cardiovascular Research, Berlin, 10115, Germany. michael.schupp@charite.de.

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.Fatty liver is one of the major features of metabolic syndrome and its development is associated with deregulation of systemic lipid and glucose homeostasis. Here Heidenreich et al. show that retinol saturase is implicated in hepatic lipid metabolism by regulating the activity of the transcription factor ChREBP.

PMID:
28855500
PMCID:
PMC5577314
DOI:
10.1038/s41467-017-00430-w
[Indexed for MEDLINE]
Free PMC Article

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