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JBC:胰岛素如何调节全反式维甲酸合成?

来源:生物谷 2015-01-29 09:59

                                            
2015年1月29日讯 /生物谷BIOON/ --近日,国际生物学期刊the journal of biological chemistry在线发表了来自美国科学家的一项最近研究成果。研究人员发现机体能量水平能够通过视黄醇脱氢酶调控全反式维甲酸的生物合成,通过实验证明了全反式维甲酸与胰岛素信号途径的相互关系。这一研究成果对研究胰岛素相关疾病如二型糖尿病等具有一定意义。
 
全反式维甲酸(atRA)是一种来自视黄醇(维生素A)的自体有效物质,它能够调节能量平衡减少肥胖。Kristin M. Obrochta等人发现atRA的合成会受到机体能量水平的调节,这种作用主要是通过调节视黄醇脱氢酶(Rdh)的表达实现的。研究人员在给小鼠饥饿再进食6小时后发现,与饥饿16小时的小鼠相比,肝脏和棕色脂肪中Rdh1的表达水平下降了约80%~90%,在肝脏,胰腺和肾脏中Rdh10的表达下降了约45%~63%,同时发现肝脏内atRA的表达水平也下降。口服葡萄糖或腹腔注射胰岛素都会导致肝脏内Rdh1和Rdh10表达下降50%。
 
研究人员通过体外细胞培养发现,移除培养基中的血清,会增加Rdh10和Rdh16(小鼠Rdh1的同源蛋白)表达,但进行胰岛素刺激后,Rdh10和Rdh16的表达水平又发生下降。通过对机制探讨发现能量水平可以通过胰岛素和Foxo1调节Rdh表达以及atRA的生物合成。
 
综上所述,该研究发现能量水平能够调节全反式维甲酸合成,这种调节作用主要是通过胰岛素和Foxo1影响Rdh表达实现的。这一研究成果对研究全反式维甲酸与胰岛素信号通路的相互作用在II型糖尿病等胰岛素相关疾病中的作用具有一定意义。(生物谷Bioon.com)
 
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Insulin Regulates Retinol Dehydrogenase Expression and all-trans-Retinoic Acid Biosynthesis through FoxO1
 
Kristin M. Obrochta, Charles R. Krois, Benito Campos and Joseph L. Napoli
 
All-trans-retinoic acid (atRA), an autocoid derived from retinol (vitamin A), regulates energy balance and reduces adiposity. We show that energy status regulates atRA biosynthesis at the rate-limiting step, catalyzed by retinol dehydrogenases (Rdh). Six hr after re-feeding, Rdh1 expression decreased 80-90% in liver and brown adipose tissue and Rdh10 expression decreased 45-63% in liver, pancreas and kidney, all relative to mice fasted 16 hr. atRA in liver decreased 44% 3 hr after reduced Rdh expression. Oral gavage with glucose or injection with insulin decreased Rdh1 and Rdh10 mRNA 50% or greater in mouse liver. Removing serum from the medium of the human hepatoma cell line HepG2 increased Rdh10 and Rdh16 (human Rdh1 ortholog) mRNA expression 2-3 fold by 4 hr, by increasing transcription and stabilizing mRNA. Insulin decreased Rdh10 and Rdh16 mRNA in HepG2 cells incubated in serum-free medium, through inhibiting transcription and destabilizing mRNA. Insulin action required PI3K and Akt, which suppressed FoxO1. Serum removal increased atRA biosynthesis 4-fold from retinol in HepG2 cells, whereas dominant negative FoxO1 prevented the increase. Thus, energy status via insulin and FoxO1 regulate Rdh expression and atRA biosynthesis. These results reveal mechanisms for regulating atRA biosynthesis and the opposing effects of atRA and insulin on gluconeogenesis, and also suggest an interaction between atRA and insulin signaling-related diseases, such as type II diabetes and cancer.
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