PHD3 regulates glucose metabolism by suppressing stress-induced signalling and optimising gluconeogenesis and insulin signalling in hepatocytes.
PHD3 regulates glucose metabolism by suppressing stress-induced signalling and optimising gluconeogenesis and insulin signalling in hepatocytes.
复制标题
DOI：
10.1038/s41598-018-32575-z
复制
发表时间：
2018-09-24
影响因子：
4.6
通讯作者：
Matsumoto M
中科院分区：
文献类型：
--
作者：
Yano H;Sakai M;Matsukawa T;Yagi T;Naganuma T;Mitsushima M;Iida S;Inaba Y;Inoue H;Unoki-Kubota H;Kaburagi Y;Asahara SI;Kido Y;Minami S;Kasuga M;Matsumoto M
肝脏中胰高血糖素介导的基因转录对于维持葡萄糖稳态至关重要。促进糖异生基因的诱导和阻断肝细胞中胰岛素受体底物（Irs）2的表达参与了2型糖尿病的发病机制。然而，胰高血糖素信号调节肝细胞代谢的分子机制尚不完全清楚。我们之前的研究表明，胰高血糖素诱导的糖异生基因转录需要一个由一般控制非抑制蛋白5、共同调节因子cAMP反应元件结合蛋白结合蛋白/p300与Glu/Asp-rich羧基末端结构域2相互作用的反激活因子和蛋白激酶a组成的可诱导禁食的信号模块。本研究旨在通过检测胰高血糖素诱导的潜在靶基因，确定该模块在肝细胞中的下游效应物。其中一个基因是脯氨酸羟化酶结构域（prolyl hydroxylase domain， PHD）3，它通过不依赖脯氨酸羟化酶的方式抑制i -κB激酶-核因子-κB通路来抑制应激信号传导，维持胰岛素信号传导。过氧化物酶体增殖体激活受体γ共激活因子1α-诱导的糖异生也需要PHD3，这依赖于脯氨酸羟化酶的活性，表明PHD3在胰高血糖素和胰岛素的作用下调节代谢。这些发现表明，胰高血糖素诱导的PHD3通过抑制应激信号和优化肝细胞中的糖异生和胰岛素信号来调节葡萄糖代谢。
Glucagon-mediated gene transcription in the liver is critical for maintaining glucose homeostasis. Promoting the induction of gluconeogenic genes and blocking that of insulin receptor substrate (Irs)2 in hepatocytes contributes to the pathogenesis of type 2 diabetes. However, the molecular mechanism by which glucagon signalling regulates hepatocyte metabolism is not fully understood. We previously showed that a fasting-inducible signalling module consisting of general control non-repressed protein 5, co-regulator cAMP response element-binding protein binding protein/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2, and protein kinase A is required for glucagon-induced transcription of gluconeogenic genes. The present study aimed to identify the downstream effectors of this module in hepatocytes by examining glucagon-induced potential target genes. One of these genes was prolyl hydroxylase domain (PHD)3, which suppressed stress signalling through inhibition of the IκB kinase–nuclear factor-κB pathway in a proline hydroxylase-independent manner to maintain insulin signalling. PHD3 was also required for peroxisome proliferator–activated receptor γ coactivator 1α-induced gluconeogenesis, which was dependent on proline hydroxylase activity, suggesting that PHD3 regulates metabolism in response to glucagon as well as insulin. These findings demonstrate that glucagon-inducible PHD3 regulates glucose metabolism by suppressing stress signalling and optimising gluconeogenesis and insulin signalling in hepatocytes.
登录
查看更多内容
影响因子：
82.9
作者：
Arkan, MC;Hevener, AL;Karin, M
通讯作者：
Karin, M
影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.1
作者：
Fleischmann, M;Iynedjian, PB
通讯作者：
Iynedjian, PB
影响因子：
56.9
作者：
Ivan, M;Kondo, K;Kaelin, WG
通讯作者：
Kaelin, WG