A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death.

IF 9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EMBO Molecular Medicine Pub Date : 2024-09-11 DOI:10.1038/s44321-024-00130-1

Céline Van Dender,Steven Timmermans,Ville Paakinaho,Tineke Vanderhaeghen,Jolien Vandewalle,Maarten Claes,Bruno Garcia,Bart Roman,Jan De Waele,Siska Croubels,Karolien De Bosscher,Philip Meuleman,Antoine Herpain,Jorma J Palvimo,Claude Libert

{"title":"A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death.","authors":"Céline Van Dender,Steven Timmermans,Ville Paakinaho,Tineke Vanderhaeghen,Jolien Vandewalle,Maarten Claes,Bruno Garcia,Bart Roman,Jan De Waele,Siska Croubels,Karolien De Bosscher,Philip Meuleman,Antoine Herpain,Jorma J Palvimo,Claude Libert","doi":"10.1038/s44321-024-00130-1","DOIUrl":null,"url":null,"abstract":"In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has a strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α depletion in hepatocytes dramatically increases sepsis lethality, steatosis, and organ damage and prevents an adequate response to IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in tolerance to sepsis. In conclusion, hepatic HNF4α activity is decreased during sepsis, causing PPARα downregulation, metabolic problems, and a disturbed IL6-mediated acute phase response. The findings provide new insights and therapeutic options in sepsis.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"10 1","pages":""},"PeriodicalIF":9.0000,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"EMBO Molecular Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s44321-024-00130-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

Abstract

In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has a strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α depletion in hepatocytes dramatically increases sepsis lethality, steatosis, and organ damage and prevents an adequate response to IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in tolerance to sepsis. In conclusion, hepatic HNF4α activity is decreased during sepsis, causing PPARα downregulation, metabolic problems, and a disturbed IL6-mediated acute phase response. The findings provide new insights and therapeutic options in sepsis.

查看原文本刊更多论文

HNF4α在多微生物败血症相关代谢重编程和死亡中的关键作用

在败血症中，有限的食物摄入量和增加的能量消耗会诱发饥饿反应，而肝脏 PPARα 表达的快速下降会损害这种反应，PPARα 是细胞内游离脂肪酸分解过程中必不可少的转录因子。PPARα 下调的上游机制尚不清楚。我们发现脓毒症会导致肝脏 HNF4α 逐渐丧失功能，而 HNF4α 对包括 PPARα 在内的几种重要核受体的表达有很大影响。肝细胞中 HNF4α 的耗竭会显著增加败血症致死率、脂肪变性和器官损伤，并阻止对 IL6 的充分反应，而 IL6 对肝脏再生和存活至关重要。HNF4α激动剂能在所有水平上防止败血症，而与细菌负荷无关，这表明HNF4α对败血症的耐受性至关重要。总之，脓毒症期间肝脏 HNF4α 活性降低，导致 PPARα 下调、代谢问题和 IL6 介导的急性期反应紊乱。这些发现为脓毒症提供了新的见解和治疗方案。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

EMBO Molecular Medicine 医学-医学：研究与实验

CiteScore

17.70

自引率

0.90%

发文量

105

审稿时长

4-8 weeks

期刊介绍： EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)