Novel functions of Retinol Saturase in glucose sensing

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Retinol Saturase (RetSat) is an oxidoreductase and highly expressed in tissues involved in glucose and fatty acid metabolism such as liver and adipose tissue. RetSat catalyzes the reduction of retinol to 13,14-dihydroretinol. We could show that RetSat is regulated by peroxisome proliferator activated receptor gamma (PPARgamma) and enhances adipocyte differentiation (Schupp&Lazar, PNAS 2009). Moreover, we found that RetSat controls liver metabolism by regulating the activity of the glucose-sensing transcription factor carbohydrate response element binding protein (ChREBP) (Heidenreich&Schupp, Nat Commun 2017). Both functions were independent of 13,14-dihydroretinol generation, suggesting that RetSat catalyzes other, yet unknown reactions. In this proposal we will dissect the underlying molecular mechanisms (ChREBP-dependent and independent effects, the role of post-translational RetSat modification, and a RetSat in vitro activity assay for the identification of alternative substrates) that, based on our preliminary data, we identified as functionally relevant. These mechanistic approaches will be complemented with the characterization of newly-generated inducible RetSat knockout mouse models for specific tissues. Findings from this proposal will decipher important aspects of RetSat's biology and contribute to our understanding of how RetSat affects ChREBP activity. Moreover, the obtained insights may provide the rationale for establishing RetSat as a pharmacological target for metabolic diseases and its associated complications.