CrbpI Modulates Glucose Homeostasis and Pancreas 9-cis-Retinoic Acid Concentrations
CrbpI Modulates Glucose Homeostasis and Pancreas 9-cis-Retinoic Acid Concentrations
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DOI：
10.1128/mcb.05516-11
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发表时间：
2011-08-01
影响因子：
5.3
通讯作者：
Napoli, Joseph L.
中科院分区：
文献类型：
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作者：
Kane, Maureen A.;Folias, Alexandra E.;Napoli, Joseph L.
由Rpb 1编码的细胞视黄醇结合蛋白I（CrbpI）作为视黄醇稳态的伴侣，但其生理作用仍不完全清楚。我们发现Rbp 1（-/-）小鼠在多个组织中破坏了类维生素A的体内平衡，9-顺式维甲酸（9 cRA）异常高，这是一种胰腺自分泌物，可减弱葡萄糖刺激的胰岛素分泌。Rbp 1（-/-）胰腺具有增加的视黄醇和Rpb 2 mRNA（编码CrbpII）的强烈异位表达：两者均有助于增加β细胞9 cRA生物合成。Rbp 1（-/-）胰腺中的9 cRA抵抗餐后和葡萄糖诱导的降低。Rbp 1（-/-）小鼠具有参与葡萄糖感知和胰岛素分泌的基因的缺陷性胰岛表达，以及胰岛α细胞浸润，其有助于减少葡萄糖刺激的胰岛素分泌、高胰高血糖素分泌、异常高的胰岛生成率和高血糖症。富含维生素A的饮食（如标准食物饮食）会增加胰腺9 cRA并损害葡萄糖耐量。Crbp 1减弱了维生素A（视黄醇）对葡萄糖耐量的负面影响，无论饮食中视黄醇含量如何。rbp 1（-/-）小鼠脂肪酸氧化速率增加，当喂食高脂饮食时，它们能够抵抗肥胖。因此，葡萄糖稳态和能量代谢依赖于Rbp 1的表达及其对胰腺视黄醇和自泌激素9 cRA的调节。
Cellular retinol-binding protein type I (CrbpI), encoded by Rpb1, serves as a chaperone of retinol homeostasis, but its physiological effects remain incompletely understood. We show here that the Rbp1(-/-) mouse has disrupted retinoid homeostasis in multiple tissues, with abnormally high 9-cis-retinoic acid (9cRA), a pancreas autacoid that attenuates glucose-stimulated insulin secretion. The Rbp1(-/-) pancreas has increased retinol and intense ectopic expression of Rpb2 mRNA, which encodes CrbpII: both would contribute to increased beta-cell 9cRA biosynthesis. 9cRA in Rbp1(-/-) pancreas resists postprandial and glucose-induced decreases. Rbp1(-/-) mice have defective islet expression of genes involved in glucose sensing and insulin secretion, as well as islet alpha-cell infiltration, which contribute to reduced glucose-stimulated insulin secretion, high glucagon secretion, an abnormally high rate of gluconeogenesis, and hyperglycemia. A diet rich in vitamin A (as in a standard chow diet) increases pancreas 9cRA and impairs glucose tolerance. Crbp1 attenuates the negative impact of vitamin A (retinol) on glucose tolerance, regardless of the dietary retinol content. Rbp1(-/-) mice have an increased rate of fatty acid oxidation and resist obesity when fed a high-fat diet. Thus, glucose homeostasis and energy metabolism rely on Rbp1 expression and its moderation of pancreas retinol and of the autacoid 9cRA.