Novel functions of Retinol Saturase in glucose sensing

视黄醇饱和酶（RetSat）是一种氧化还原酶，在肝脏和脂肪组织等参与葡萄糖和脂肪酸代谢的组织中高度表达。RetSat催化视黄醇还原为13,14-二氢视黄醇。我们可以证明RetSat受过氧化物酶体增殖物激活受体γ (PPARgamma)调控，并增强脂肪细胞分化（Schupp&Lazar, PNAS 2009）。此外，我们发现RetSat通过调节葡萄糖感应转录因子碳水化合物反应元件结合蛋白（ChREBP）的活性来控制肝脏代谢（Heidenreich&Schupp, Nat comm 2017）。这两种功能都独立于13,14-二氢视黄醇的生成，这表明RetSat催化了其他未知的反应。在本提案中，我们将分析潜在的分子机制（chrebp依赖和独立效应，翻译后RetSat修饰的作用，以及RetSat体外活性测定用于鉴定替代底物），根据我们的初步数据，我们认为这些机制与功能相关。这些机制方法将与新生成的用于特定组织的诱导型RetSat敲除小鼠模型的特性相辅相成。这项提案的发现将破译RetSat生物学的重要方面，并有助于我们了解RetSat如何影响ChREBP活性。此外，获得的见解可能为将RetSat建立为代谢性疾病及其相关并发症的药理学靶点提供理论依据。

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.