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.

中文翻译：

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HNF4α 在多种微生物脓毒症相关的代谢重编程和死亡中起关键作用。


在脓毒症中，食物摄入受限和能量消耗增加会诱发饥饿反应，肝脏 PPARα 的表达迅速下降会损害这种反应，PPARα 是游离脂肪酸细胞内分解代谢所必需的转录因子。这种 PPARα 下调的上游机制尚不清楚。我们发现脓毒症会导致 HNF4α 进行性肝功能丧失，这对包括 PPARα 在内的几种重要核受体的表达有很大影响。肝细胞中 HNF4α 的耗竭会显著增加脓毒症致死率、脂肪变性和器官损伤，并阻止对 IL6 的充分反应，这对肝脏再生和存活至关重要。HNF4α 激动剂可在各个层面预防脓毒症，而不受细菌载量的影响，这表明 HNF4α 对脓毒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选择。