急性内质网膜应激通过刺激MAPK酸酶3降解来抑制肝脏葡萄糖生成
Xiaohua Huang1,2, Heng Zhu1,2, Wei Lu1
1Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China.
International journal of molecular sciences
|November 14, 2023
概括
急性内质网膜 (ER) 压力通过PERK信号传递来降低MAPK酸酶3 (MKP-3) 水平,抑制肝脏葡萄糖的产生. MKP-3是药物诱导性肝损伤 (DILI) 低血糖症的潜在治疗标.
科学领域:
- 肝病学 肝病学是一种肝病学.
- 细胞应激反应的应激反应
- 代谢调节 代谢调节 代谢调节
背景情况:
- 药物诱导性肝损伤 (DILI) 是与内质网膜 (ER) 压力相关的重大健康问题.
- 已知急性ER压力会损害肝脏葡萄糖生成,并可能导致低血糖症,但潜在的机制仍然难以捉摸.
- MAPK酸酶3 (MKP-3) 在促进肝脏葡萄糖生成中起着至关重要的作用.
研究的目的:
- 为了研究MKP-3在ER中MKP-3在ER中所扮演的角色,以压力诱导的肝脏葡萄糖生成的抑制.
- 阐明急性ER压力如何调节MKP-3表达及其对葡萄糖代谢的影响.
主要方法:
- 肝细胞和小鼠肝脏模型被用于研究尼卡米辛诱导的急性ER压力的影响.
- 分析葡萄糖生成,葡萄糖生产,血糖水平和MKP-3蛋白质表达.
- 使用Mkp-3缺陷和肝脏特异性的Mkp-3绝杀小鼠.
- 研究了PERK信号通路的参与.
主要成果:
- 急性ER压力显著抑制了葡萄糖生成,并减少了肝细胞和小鼠肝脏中的葡萄糖产量.
- ER压力导致MKP-3蛋白水平降低.
- 缺乏Mkp-3取消了ER压力诱导的葡萄糖生成和低血糖抑制.
- PERK激活降低了MKP-3蛋白水平,而PERK抑制阻止了这种降低.
结论:
- 急性ER压力通过PERK通路促进MKP-3降解来抑制肝脏葡萄糖生成.
- MKP-3是ER压力诱导的低血糖症的关键调解者.
- MKP-3代表了管理与DILI相关的低血糖症的潜在治疗标.
相关概念视频
01:25cAMP-dependent Protein Kinase Pathways
6.4K
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
6.4K
01:07MAPK Signaling Cascades
5.6K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.6K
01:37The Unfolded Protein Response
4.7K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
4.7K
01:31Regulation of the Unfolded Protein Response
2.4K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.4K
01:22PI3K/mTOR/AKT Signaling Pathway
3.6K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
3.6K
01:58Cell Specific Gene Expression
13.6K
Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
13.6K