Retinaldehyde Dehydrogenase 1 Coordinates Hepatic Gluconeogenesis and Lipid Metabolism
Retinaldehyde Dehydrogenase 1 Coordinates Hepatic Gluconeogenesis and Lipid Metabolism
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DOI：
10.1210/en.2011-2104
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发表时间：
2012-07-01
期刊：
影响因子：
4.8
通讯作者：
Plutzky, Jorge
中科院分区：
文献类型：
--
作者：
Kiefer, Florian W.;Orasanu, Gabriela;Plutzky, Jorge
最近的数据将维生素 A 及其类视黄醇代谢物与脂肪生成、胰岛素敏感性和葡萄糖稳态的调节联系起来。类视黄醇代谢受到酶网络的严格控制，其中视黄醛脱氢酶 (Aldh1-3) 是将视黄醛转化为视黄酸的限速酶。 Aldh1a1 缺陷小鼠可以免受饮食引起的肥胖和糖尿病的影响。在这里，我们研究了 Aldh1a1 和类视黄醇轴是否独立于肥胖而调节肝脏葡萄糖和脂质代谢。在体外肝细胞中以及体内喂养、体重匹配的 Aldh1a1 缺陷小鼠与野生型 (WT) 小鼠的肝细胞中，分析了 Aldh1a1 和类视黄醇通路对葡萄糖稳态和脂质代谢的影响。由于肝葡萄糖产生减弱，与 WT 对照组相比，Aldh1a1 缺陷小鼠的空腹血糖浓度显着降低。与 WT 肝脏相比，Aldh1a1 缺陷型肝脏中关键糖异生酶的表达以及 Forkhead box O1 的活性均降低。在体外，类视黄醇或 cAMP 激动剂刺激显着诱导 WT 中的糖异生，但不诱导 Aldh1a1 缺陷的原代肝细胞。 Aldh1a1 缺陷增加 AMP 激活蛋白激酶 α 活性，降低 AMP 激活蛋白激酶 α 脂肪生成靶点的表达，并显着减弱肝脏三酰甘油合成。在代谢笼研究中，与 WT 对照组相比，缺乏 Aldh1a1 的瘦小鼠表现出耗氧量增加和呼吸商降低，这与骨骼肌中脂肪酸氧化标记物表达增加一致。总而言之，这项工作确立了类视黄醇代谢在体内葡萄糖稳态中的作用，以及 Aldh1a1 作为独立于肥胖的糖异生和脂质代谢的新决定因素。 （内分泌学153：3089-3099，2012）
Recent data link vitamin A and its retinoid metabolites to the regulation of adipogenesis, insulin sensitivity, and glucose homeostasis. Retinoid metabolism is tightly controlled by an enzymatic network in which retinaldehyde dehydrogenases (Aldh1-3) are the rate-limiting enzymes that convert retinaldehyde to retinoic acid. Aldh1a1-deficient mice are protected from diet-induced obesity and hence diabetes. Here we investigated whether Aldh1a1 and the retinoid axis regulate hepatic glucose and lipid metabolism independent of adiposity. The impact of Aldh1a1 and the retinoid pathway on glucose homeostasis and lipid metabolism was analyzed in hepatocytes in vitro and in chow-fed, weight-matched Aldh1a1-deficient vs. wild-type (WT) mice in vivo. Aldh1a1-deficient mice displayed significantly decreased fasting glucose concentrations compared with WT controls as a result of attenuated hepatic glucose production. Expression of key gluconeogenic enzymes as well as the activity of Forkhead box O1 was decreased in Aldh1a1-deficient vs. WT livers. In vitro, retinoid or cAMP agonist stimulation markedly induced gluconeogenesis in WT but not Aldh1a1-deficient primary hepatocytes. Aldh1a1 deficiency increased AMP-activated protein kinase alpha activity, decreased expression of lipogenic targets of AMP-activated protein kinase alpha and significantly attenuated hepatic triacylglycerol synthesis. In metabolic cage studies, lean Aldh1a1-deficient mice manifested enhanced oxygen consumption and reduced respiratory quotient vs. WT controls, consistent with increased expression of fatty acid oxidation markers in skeletal muscle. Taken together, this work establishes a role for retinoid metabolism in glucose homeostasis in vivo and for Aldh1a1 as a novel determinant of gluconeogenesis and lipid metabolism independent of adiposity. (Endocrinology 153: 3089-3099, 2012)