Retinoids synergize with insulin to induce hepatic Gck expression.
Retinoids synergize with insulin to induce hepatic Gck expression.
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类维生素类似于胰岛素协同诱导肝GCK表达。
DOI：
10.1042/bj20082368
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发表时间：
2009-05-01
期刊：
影响因子：
--
通讯作者：
Ross AC
中科院分区：
文献类型：
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作者：
Chen G;Zhang Y;Lu D;Li NQ;Ross AC
肝脏葡萄糖激酶(GK)在维持血糖稳态中起着关键作用。许多刺激物通过控制GK的基因转录来调节其活性。我们假设内源性亲脂分子调节肝脏GCK的表达。从大鼠肝脏中提取亲脂分子，皂化后重组为亲脂提取物(LE)。LE与胰岛素协同诱导原代肝细胞，而不是β细胞，GCK以SREBP1c(固醇调节元件结合蛋白1c)非依赖的方式表达。GCK mRNA的显著诱导导致GK活性显著升高。纯化后的活性成分经MS鉴定为视黄醇和视黄醇。维甲酸类化合物通过激活RAR[RA(维甲酸)受体]和RXR(维甲酸X受体)协同胰岛素诱导GCK的表达。抑制RAR的激活可完全消除视网膜的作用。VAD[VA(维生素A)缺乏]饲料喂养的Zucker瘦肉大鼠肝脏GK比活力和GCK mRNA水平显著低于VAS(VA充足)饲料喂养的大鼠。此外，饲喂VAD饲料的SD大鼠肝脏GCK mRNA的表达低于饲喂VA边际饲料、适量饲料和添加VA饲料的大鼠。VAD大鼠经腹膜腔注射维甲酸后，GCK基因表达下调的程度增加。此外，静脉注射维甲酸可迅速增加VAS对照组大鼠肝脏GCK的表达。了解介导协同作用的潜在机制可能有助于制定糖尿病患者的治疗策略。
Hepatic GK (glucokinase) plays a key role in maintaining glucose homoeostasis. Many stimuli regulate GK activity by controlling its gene transcription. We hypothesized that endogenous lipophilic molecules modulate hepatic Gck expression. Lipophilic molecules were extracted from rat livers, saponified and re-constituted as an LE (lipophilic extract). LE synergized with insulin to induce primary hepatocyte, but not β-cell, Gck expression in an SREBP-1c (sterol-regulatory-element-binding protein-1c)-independent manner. The dramatic induction of Gck mRNA resulted in a significant increase in GK activity. Subsequently, the active molecules were identified as retinol and retinal by MS after the purification of the active LE fractions. Retinoids synergized with insulin to induce Gck expression by the activation of both RAR [RA (retinoic acid) receptor] and RXR (retinoid X receptor). Inhibition of RAR activation completely abolished the effect of retinal. The hepatic GK specific activity and Gck mRNA levels of Zucker lean rats fed with a VAD [VA (vitamin A)-deficient] diet were significantly lower than those of rats fed with VAS (VA-sufficient) diet. Additionally, the hepatic Gck mRNA expression of Sprague–Dawley rats fed with a VAD diet was lower than that of rats fed with VA-marginal, -adequate or -supplemented diets. The reduced expression of Gck mRNA was increased after an intraperitoneal dose of RA in VAD rats. Furthermore, an intravenous injection of RA rapidly raised hepatic Gck expression in rats fed with a VAS control diet. Understanding the underlying mechanism that mediates the synergy may be helpful for developing a treatment strategy for patients with diabetes.