研究动态
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肝细胞的TIPE2是一种由禁食引起的Raf-1失活剂,促使肝脏糖异生以保持葡萄糖平衡。

Hepatocyte TIPE2 is a fasting-induced Raf-1 inactivator that drives hepatic gluconeogenesis to maintain glucose homeostasis.

发表日期:2023 Sep 15
作者: Yan Tao, Jingyuan Zhao, Jilong Yin, Zixin Zhou, Huijie Li, Jinhao Zang, Tianci Wang, Yalin Wang, Chun Guo, Faliang Zhu, Shen Dai, Fuwu Wang, Hui Zhao, Haiting Mao, Fengming Liu, Lining Zhang, Qun Wang
来源: METABOLISM-CLINICAL AND EXPERIMENTAL

摘要:

肝脏在禁食和进食周期中调节代谢平衡。肝脏对禁食的适应是在多个水平上精确调节的。肿瘤坏死因子-α诱导的蛋白8样2(TIPE2)是负调节器,能减少几种肝脏病理,但其在肝脏代谢中的生理作用尚不明确。研究检测了小鼠肝脏在禁食-进食周期中的TIPE2表达。研究检测了TIPE2基因敲除小鼠、肝特异性TIPE2基因敲除小鼠、肝特异性TIPE2过表达小鼠的禁食血糖和丙酮酸耐受性试验。通过评估来自这些小鼠的原代肝细胞或肝组织的葡萄糖产生、脂肪积累、基因表达和调节途径情况,分析了TIPE2与Raf-1的相互作用以及PPAR-α对TIPE2转录的调节。通过基因过表达或基因敲除、共免疫沉淀、Western blot、荧光素酶报告基因分析和DNA-蛋白结合实验,检测了TIPE2与Raf-1的相互作用以及TIPE2转录的调节。结果显示,TIPE2在禁食小鼠肝脏和饥饿肝细胞中上调表达,与葡萄糖生成基因呈正相关。肝特异性TIPE2缺乏会导致小鼠在禁食时血糖稳态和葡萄糖生成能力下降,而肝脏特异性TIPE2过表达会提高小鼠的禁食血糖和肝脏葡萄糖生成。在饥饿原代肝细胞中,TIPE2与Raf-1相互作用,促进其泛素化和降解,从而导致ERK失活和FOXO1维持以维持葡萄糖生成。长时间禁食过程中,肝脏TIPE2缺乏导致ERK-mTORC1轴的异常激活,通过脂肪生物合成增加肝脏脂肪积累。在饥饿肝细胞中,PPAR-α与TIPE2启动子结合,并触发其转录表达。肝细胞中的TIPE2是PPAR-α诱导的Raf-1失活剂,能维持肝脏葡萄糖生成并防止过量的肝脏脂肪积累,在肝脏对禁食的适应中发挥有益的作用。版权所有 ©2023 Elsevier Inc.发表。
The liver regulates metabolic balance during fasting-feeding cycle. Hepatic adaptation to fasting is precisely modulated on multiple levels. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a negative regulator of immunity that reduces several liver pathologies, but its physiological roles in hepatic metabolism are largely unknown.TIPE2 expression was examined in mouse liver during fasting-feeding cycle. TIPE2-knockout mice, liver-specific TIPE2-knockout mice, liver-specific TIPE2- overexpressed mice were examined for fasting blood glucose and pyruvate tolerance test. Primary hepatocytes or liver tissues from these mice were evaluated for glucose production, lipid accumulation, gene expression and regulatory pathways. TIPE2 interaction with Raf-1 and TIPE2 transcription regulated by PPAR-α were examined using gene overexpression or knockdown, co-immunoprecipitation, western blot, luciferase reporter assay and DNA-protein binding assay.TIPE2 expression was upregulated in fasted mouse liver and starved hepatocytes, which was positively correlated with gluconeogenic genes. Liver-specific TIPE2 deficiency impaired blood glucose homeostasis and gluconeogenic capacity in mice upon fasting, while liver-specific TIPE2 overexpression elevated fasting blood glucose and hepatic gluconeogenesis in mice. In primary hepatocytes upon starvation, TIPE2 interacted with Raf-1 to accelerate its ubiquitination and degradation, resulting in ERK deactivation and FOXO1 maintenance to sustain gluconeogenesis. During prolonged fasting, hepatic TIPE2 deficiency caused aberrant activation of ERK-mTORC1 axis that increased hepatic lipid accumulation via lipogenesis. In hepatocytes upon starvation, PPAR-α bound with TIPE2 promoter and triggered its transcriptional expression.Hepatocyte TIPE2 is a PPAR-α-induced Raf-1 inactivator that sustains hepatic gluconeogenesis and prevents excessive hepatic lipid accumulation, playing beneficial roles in hepatocyte adaptation to fasting.Copyright © 2023. Published by Elsevier Inc.