Retinol saturase coordinates liver metabolism by regulating ChREBP activity

Steffi Heidenreich, Nicole Witte, Pamela Weber, Isabel Goehring, Alexander Tolkachov, Christian von Loeffelholz, Stephanie Döcke, Michael Bauer, Martin Stockmann, Andreas F H Pfeiffer, Andreas L Birkenfeld, Matthias Pietzke, Stefan Kempa, Matthias Muenzner, Michael Schupp

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)
99 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)384
JournalNature Communications
Volume8
Issue number1
Early online date30 Aug 2017
DOIs
Publication statusPublished - 30 Aug 2017

Keywords

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism
  • Fatty Liver/metabolism
  • Glucose/metabolism
  • Hepatocytes/metabolism
  • Humans
  • Lipid Metabolism
  • Liver/metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidoreductases Acting on CH-CH Group Donors/genetics
  • Triglycerides/blood

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