Novel functions of Retinol Saturase in glucose sensing

视黄醇饱和酶（RetSat）是一种氧化还原酶，在参与葡萄糖和脂肪酸代谢的组织如肝脏和脂肪组织中高度表达。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）调节并增强脂肪细胞分化（Schupp&Lazar，PNAS 2009）。此外，我们发现RetSat通过调节葡萄糖敏感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 Commun 2017）。这两种功能都独立于13，14-二氢视黄醇的产生，表明RetSat催化其他未知的反应。在这项提案中，我们将剖析潜在的分子机制（ChREBP依赖性和独立的影响，翻译后RetSat修饰的作用，和RetSat在体外活性测定的替代底物的识别），根据我们的初步数据，我们确定为功能相关。这些机制的方法将补充新生成的诱导型RetSat敲除小鼠模型的特定组织的表征。这项提案的发现将破译RetSat生物学的重要方面，并有助于我们理解RetSat如何影响ChREBP活性。此外，所获得的见解可以为将RetSat确立为代谢疾病及其相关并发症的药理学靶点提供理论基础。

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.