Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, China.
Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China.
J Cell Mol Med. 2020 Mar;24(6):3611-3624. doi: 10.1111/jcmm.15053. Epub 2020 Feb 12.
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.
高脂肪饮食（HFD）可导致肥胖、2 型糖尿病（T2DM），并增加心血管疾病和癌症的并发风险。胰岛素抵抗（IR）被认为是这些疾病的“共同土壤”。此外，高脂肪饮食的人群表现出受抑制的糖酵解和增强的脂肪酸氧化，这就是所谓的代谢重编程。然而，HFD 诱导的代谢重编程与 IR 之间的关系仍不清楚。在这里，我们证明了在高脂肪饮食喂养 16 周的小鼠肝脏组织中 PANK1 和 miR-107 上调，并参与了棕榈酸（PA）孵育诱导的代谢重编程。重要的是，miR-107 位于 PANK1 基因的内含子中，通过靶向 AML12 细胞中的窖蛋白-1，促进了 PA 孵育时的 IR。此外，我们发现 HFD 增强了 P53 的表达，并用 nutlin-3a 激活 P53，在转录水平上同时诱导 PANK1 和 miR-107 的表达，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，我们的研究结果揭示了 P53 调节代谢的新机制。此外，这些结果区分了 PANK1 及其内含子 miR-107 在代谢调节中的不同作用，这将为代谢疾病的治疗提供更准确的干预靶点。
