Retinol Esterification by DGAT1 Is Essential for Retinoid Homeostasis in Murine Skin
Retinol Esterification by DGAT1 Is Essential for Retinoid Homeostasis in Murine Skin
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DOI：
10.1074/jbc.m807503200
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发表时间：
2009-02-13
影响因子：
4.8
通讯作者：
Farese, Robert V., Jr.
中科院分区：
文献类型：
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作者：
Shih, Michelle Y. S.;Kane, Maureen A.;Farese, Robert V., Jr.
维甲酸(RA)是一种强大的信号分子，在许多生物过程中都是必不可少的，其水平受到一些机制的严格调控，但对这些机制的了解还不多。视黄醇前体(维生素A)合成RA是其重要的调控机制。因此，视黄醇与脂肪酰基部分的酯化反应生成视黄酸酯(视黄醇的主要储存形式)也可能调节RA水平。在这里，我们发现中性脂质合成酶酰辅酶A：二酰甘油酰基转移酶1(DGAT1)是小鼠皮肤中主要的酰基辅酶A：视黄醇酰基转移酶(ARAT)。当饮食中的视黄醇丰富时，DGAT1缺乏会导致皮肤中RA水平升高和周期性脱发；两者都可以通过饮食中缺乏视黄醇来预防。此外，DGAT1缺陷皮肤对局部应用视黄醇的敏感性增强。该酶在表皮中的特异性缺失会导致脱发，这表明DGAT1对RA动态平衡的调节在表皮中是自主的。这些发现表明，DGAT1在皮肤中起着ARAT的作用，在那里它维持维甲酸的动态平衡，防止维甲酸的毒性。我们的发现可能对用调节类风湿因子信号的药物治疗人类皮肤或毛发疾病有启发意义。
Retinoic acid (RA) is a potent signaling molecule that is essential for many biological processes, and its levels are tightly regulated by mechanisms that are only partially understood. The synthesis of RA from its precursor retinol (vitamin A) is an important regulatory mechanism. Therefore, the esterification of retinol with fatty acyl moieties to generate retinyl esters, the main storage form of retinol, may also regulate RA levels. Here we show that the neutral lipid synthesis enzyme acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) functions as the major acyl-CoA: retinol acyltransferase (ARAT) in murine skin. When dietary retinol is abundant, DGAT1 deficiency results in elevated levels of RA in skin and cyclical hair loss; both are prevented by dietary retinol deprivation. Further, DGAT1-deficient skin exhibits enhanced sensitivity to topically administered retinol. Deletion of the enzyme specifically in the epidermis causes alopecia, indicating that the regulation of RA homeostasis by DGAT1 is autonomous in the epidermis. These findings show that DGAT1 functions as an ARAT in the skin, where it acts to maintain retinoid homeostasis and prevent retinoid toxicity. Our findings may have implications for human skin or hair disorders treated with agents that modulate RA signaling.