Lactate-Dependent HIF1A Transcriptional Activation Exacerbates Severe Acute Pancreatitis Through the ACSL4/LPCAT3/ALOX15 Pathway Induced Ferroptosis

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Tingyuan Zhang, Xiaopei Huang, Shengnan Feng, Huanzhang Shao
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Abstract

Acute pancreatitis (AP) is a common emergency in the digestive system, and in severe cases, it can progress to severe acute pancreatitis (SAP), with a mortality rate of up to 30%, representing a dire situation. SAP in mice was induced by l-arginine (l-Arg). HE, IHC, WB and ELISA were used to study the role and regulation of HIF1A in SAP. At the same time, QPCR, WB, CHIP-QPCR and luciferase report were used to explore the specific mechanism of HIF1A regulation of SAP in vitro. The research results indicate that following SAP induction, the pancreatic tissue of mice exhibited significant glycolytic abnormalities, accompanied by a marked upregulation of HIF1A expression. This led to apparent damage in the pancreatic tissue, lungs, and kidneys. However, in sh-HIF1A mice, the degree of these injuries was significantly alleviated, along with a reduction in the production of inflammatory factors, oxidative products, and lipid peroxidation markers. This suggests that HIF1A plays a crucial role in the inflammatory and oxidative stress processes during SAP. Further exploration revealed that the absence or overexpression of HIF1A affects SAP by inducing ferroptosis through the ACSL4/LPCAT3/ALOX15 pathway. Notably, the elevated lactate level resulting from glycolytic abnormalities further enhances the histone lactylation in the HIF1A promoter region, thereby aggravating the expression of HIF1A. Lactate-dependent HIF1A transcriptional activation exacerbates severe acute pancreatitis through the ACSL4/LPCAT3/ALOX15 pathway induced ferroptosis.

乳酸依赖性HIF1A转录激活通过ACSL4/LPCAT3/ALOX15途径诱导铁下垂加重严重急性胰腺炎
急性胰腺炎(AP)是一种常见的消化系统急症,严重者可发展为严重急性胰腺炎(SAP),死亡率高达30%,是一种可怕的情况。l-精氨酸(l-Arg)诱导小鼠SAP。采用HE、IHC、WB和ELISA等方法研究HIF1A在SAP中的作用和调控,同时采用QPCR、WB、CHIP-QPCR和荧光素酶报告等方法探讨HIF1A在体外调控SAP的具体机制。研究结果表明,在SAP诱导后,小鼠胰腺组织出现明显的糖酵解异常,并伴有HIF1A表达明显上调。这导致胰腺组织、肺和肾脏明显受损。然而,在sh-HIF1A小鼠中,这些损伤的程度显著减轻,炎症因子、氧化产物和脂质过氧化标志物的产生也减少。这表明HIF1A在SAP的炎症和氧化应激过程中起着至关重要的作用。进一步的研究发现,HIF1A的缺失或过表达通过ACSL4/LPCAT3/ALOX15途径诱导铁凋亡,从而影响SAP。值得注意的是,糖酵解异常引起的乳酸水平升高进一步增强了HIF1A启动子区域的组蛋白乳酸化,从而加重了HIF1A的表达。乳酸依赖性HIF1A转录激活通过ACSL4/LPCAT3/ALOX15途径诱导铁下垂加重严重急性胰腺炎。
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来源期刊
Journal of cellular biochemistry
Journal of cellular biochemistry 生物-生化与分子生物学
CiteScore
9.90
自引率
0.00%
发文量
164
审稿时长
1 months
期刊介绍: The Journal of Cellular Biochemistry publishes descriptions of original research in which complex cellular, pathogenic, clinical, or animal model systems are studied by biochemical, molecular, genetic, epigenetic or quantitative ultrastructural approaches. Submission of papers reporting genomic, proteomic, bioinformatics and systems biology approaches to identify and characterize parameters of biological control in a cellular context are encouraged. The areas covered include, but are not restricted to, conditions, agents, regulatory networks, or differentiation states that influence structure, cell cycle & growth control, structure-function relationships.
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