P53/PANK1/miR-107 signalling pathway spans the gap between metabolic reprogramming and insulin resistance induced by high-fat diet
P53/PANK1/miR-107 signalling pathway spans the gap between metabolic reprogramming and insulin resistance induced by high-fat diet
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P53/PANK1/miR-107信号通路跨越了代谢重编程和高脂饮食诱导的胰岛素抵抗之间的差距
DOI：
10.1111/jcmm.15053
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发表时间：
2020
影响因子：
5.3
通讯作者：
Chen Li
中科院分区：
文献类型：
--
作者：
Yang Lu;Zhang Bin;Wang Xinju;Liu Zhenhua;Li Juan;Zhang Shumiao;Gu Xiaoming;Jia Min;Guo Haitao;Feng Na;Fan Rong;Xie Manjiang;Pei Jianming;Chen Li
高脂肪饮食（HFD）会导致肥胖、二型糖尿病（T2DM）并增加心血管疾病和癌症的发病率。胰岛素抵抗（IR）被认为是这些疾病的“共同土壤”。此外，服用高脂饮食的人表现出糖酵解受到抑制，脂肪酸氧化增强，这就是所谓的代谢重编程。然而，代谢重编程与 HFD 诱导的 IR 之间的关系仍不清楚。在这里，我们证明，在 HFD 16 周的小鼠肝组织中，PANK1 和 miR-107 上调，并参与棕榈酸 (PA) 孵育诱导的代谢重编程。重要的是，PANK1 基因内含子内的 miR-107 在 PA 孵育后通过靶向 AML12 细胞中的 Caveolin-1 来促进 IR。此外，我们发现 HFD 增强了 P53 表达，并且用 nutlin-3a 激活 P53 在转录水平上同时诱导 PANK1 和 miR-107 表达，分别导致代谢重编程和 IR。一致地，用 Pifithrin-α 氢溴酸盐抑制 P53 可改善 PA 诱导的代谢重编程和 IR。因此，我们的结果揭示了 P53 调节代谢的新机制。此外，结果区分了PANK1及其内含子miR-107在代谢调节中的不同作用，将为代谢疾病的治疗提供更准确的干预靶点。
High‐fat diet (HFD) leads to obesity, type II diabetes mellitus (T2DM) and increases the coincidence of cardiovascular diseases and cancer. Insulin resistance (IR) is considered as the ‘common soil’ of those diseases. Furthermore, people on HFD showed restrained glycolysis and enhanced fatty acid oxidation, which is the so‐called metabolic reprogramming. However, the relationship between metabolic reprogramming and IR induced by HFD is still unclear. Here, we demonstrate that PANK1 and miR‐107 were up‐regulated in the liver tissue of mice on HFD for 16 weeks and involved in metabolic reprogramming induced by palmitate acid (PA) incubation. Importantly, miR‐107 within an intron of PANK1 gene facilitated IR by targeting caveolin‐1 in AML12 cells upon PA incubation. Moreover, we identify that HFD enhanced P53 expression, and activation of P53 with nutlin‐3a induced PANK1 and miR‐107 expression simultaneously in transcriptional level, leading to metabolic reprogramming and IR, respectively. Consistently, inhibition of P53 with pifithrin‐α hydrobromide ameliorated PA‐induced metabolic reprogramming and IR. Thus, our results revealing a new mechanism by which P53 regulate metabolism. In addition, the results distinguished the different roles of PANK1 and its intron miR‐107 in metabolic regulation, which will provide more accurate intervention targets for the treatment of metabolic diseases.