Obrochta Kristin M, Krois Charles R, Campos Benito, Napoli Joseph L
From the Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, University of California, Berkeley, California 94720.
From the Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, University of California, Berkeley, California 94720
J Biol Chem. 2015 Mar 13;290(11):7259-68. doi: 10.1074/jbc.M114.609313. Epub 2015 Jan 27.
All-trans-retinoic acid (atRA), an autacoid 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 h after re-feeding, Rdh1 expression decreased 80-90% in liver and brown adipose tissue and Rdh10 expression was decreased 45-63% in liver, pancreas, and kidney, all relative to mice fasted 16 h. atRA in the liver was decreased 44% 3 h 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 h, by increasing transcription and stabilizing mRNA. Insulin decreased Rdh10 and Rdh16 mRNA in HepG2 cells incubated in serum-free medium by inhibiting transcription and destabilizing mRNA. Insulin action required PI3K and Akt, which suppress 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.
全反式维甲酸（atRA）是一种由视黄醇（维生素A）衍生的自分泌物质，可调节能量平衡并减少肥胖。我们发现能量状态在视黄醇脱氢酶（RDH）催化的限速步骤中调节atRA生物合成。再喂食6小时后，相对于禁食16小时的小鼠，肝脏和棕色脂肪组织中Rdh1的表达下降了80-90%，肝脏、胰腺和肾脏中Rdh10的表达下降了45-63%。Rdh表达降低3小时后，肝脏中的atRA下降了44%。经口灌胃葡萄糖或注射胰岛素可使小鼠肝脏中Rdh1和Rdh10的mRNA降低50%或更多。从人肝癌细胞系HepG2的培养基中去除血清4小时后，通过增加转录和稳定mRNA，使Rdh10和Rdh16（人类Rdh1的直系同源物）的mRNA表达增加2-3倍。胰岛素通过抑制转录和使mRNA不稳定，降低了在无血清培养基中培养的HepG2细胞中Rdh10和Rdh16的mRNA水平。胰岛素作用需要PI3K和Akt，它们可抑制FoxO1。去除血清可使HepG2细胞中视黄醇的atRA生物合成增加4倍，而显性负性FoxO1可阻止这种增加。因此，通过胰岛素和FoxO1的能量状态调节Rdh表达和atRA生物合成。这些结果揭示了调节atRA生物合成的机制以及atRA和胰岛素对糖异生的相反作用，还提示了atRA与胰岛素信号相关疾病（如II型糖尿病和癌症）之间的相互作用。
