Ziouzenkova Ouliana, Orasanu Gabriela, Sharlach Molly, Akiyama Taro E, Berger Joel P, Viereck Jason, Hamilton James A, Tang Guangwen, Dolnikowski Gregory G, Vogel Silke, Duester Gregg, Plutzky Jorge
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nat Med. 2007 Jun;13(6):695-702. doi: 10.1038/nm1587. Epub 2007 May 27.
The metabolism of vitamin A and the diverse effects of its metabolites are tightly controlled by distinct retinoid-generating enzymes, retinoid-binding proteins and retinoid-activated nuclear receptors. Retinoic acid regulates differentiation and metabolism by activating the retinoic acid receptor and retinoid X receptor (RXR), indirectly influencing RXR heterodimeric partners. Retinoic acid is formed solely from retinaldehyde (Rald), which in turn is derived from vitamin A. Rald currently has no defined biologic role outside the eye. Here we show that Rald is present in rodent fat, binds retinol-binding proteins (CRBP1, RBP4), inhibits adipogenesis and suppresses peroxisome proliferator-activated receptor-gamma and RXR responses. In vivo, mice lacking the Rald-catabolizing enzyme retinaldehyde dehydrogenase 1 (Raldh1) resisted diet-induced obesity and insulin resistance and showed increased energy dissipation. In ob/ob mice, administrating Rald or a Raldh inhibitor reduced fat and increased insulin sensitivity. These results identify Rald as a distinct transcriptional regulator of the metabolic responses to a high-fat diet.
维生素A的代谢及其代谢产物的多种作用受到不同的类视黄醇生成酶、类视黄醇结合蛋白和类视黄醇激活核受体的严格控制。视黄酸通过激活视黄酸受体和类视黄醇X受体（RXR）来调节分化和代谢，间接影响RXR异二聚体伴侣。视黄酸仅由视黄醛（Rald）形成，而视黄醛又源自维生素A。目前，Rald在眼外没有明确的生物学作用。在此，我们表明Rald存在于啮齿动物脂肪中，与视黄醇结合蛋白（CRBP1、RBP4）结合，抑制脂肪生成并抑制过氧化物酶体增殖物激活受体γ和RXR反应。在体内，缺乏Rald分解代谢酶视黄醛脱氢酶1（Raldh1）的小鼠对饮食诱导的肥胖和胰岛素抵抗具有抵抗力，并表现出能量消耗增加。在ob/ob小鼠中，给予Rald或Raldh抑制剂可减少脂肪并提高胰岛素敏感性。这些结果确定Rald是对高脂饮食代谢反应的一种独特转录调节因子。
