A critical role for Hepatocyte Nuclear Factor 4 alpha in polymicrobial sepsis-associated metabolic reprogramming and death: ATAC-seq after CLP sepsis model. A critical role for Hepatocyte Nuclear Factor 4 alpha in polymicrobial sepsis-associated metabolic reprogramming and death: ATAC-seq after CLP sepsis model

In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in 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 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 towards IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all possible levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in disease tolerance to sepsis. In conclusion, hepatic HNF4α fails in sepsis, causing PPARα downregulation and metabolic problems and a disturbed IL6-mediated acute phase response. The data open new insights and therapeutic options in sepsis. Overall design: Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) tot determine the changes in chromatin accessibility in the liver of mice after CLP using 4 biological replicates in CLP and SHAM (control) conditions

在脓毒症中，有限的食物摄入与增加的能量消耗会诱发饥饿响应，但肝脏过氧化物酶体增殖物激活受体α（PPARα）的表达快速下调会破坏这一过程——PPARα是游离脂肪酸细胞内分解代谢所必需的转录因子。目前，该PPARα下调的上游调控机制仍不明晰。本研究发现，脓毒症会导致肝细胞核因子4α（HNF4α）逐渐丧失功能，而HNF4α对包括PPARα在内的多种重要核受体的表达具有显著调控作用。肝细胞中HNF4α的缺失会显著提升脓毒症小鼠的致死率、脂肪变性与器官损伤程度，并削弱机体对白细胞介素6（IL-6）的有效响应——而IL-6对于肝脏再生与宿主存活至关重要。肝细胞核因子4α激动剂可在所有干预水平下对脓毒症起到保护作用，且不受细菌负荷的影响，这表明HNF4α在脓毒症的疾病耐受中发挥关键调控作用。综上，脓毒症会导致肝脏HNF4α功能失常，进而引发PPARα下调、代谢紊乱以及IL-6介导的急性期反应失衡。本研究为脓毒症的发病机制提供了全新见解，并开辟了潜在的治疗方向。整体实验设计：采用转座酶可及性染色质测序（ATAC-seq），在盲肠结扎穿刺（CLP）与假手术（SHAM，对照）两组小鼠的肝脏样本中各设置4个生物学重复，以检测脓毒症诱导后小鼠肝脏染色质可及性的变化。