Center for Inflammation Research, VIB, Ghent, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
EMBO Mol Med. 2024 Oct;16(10):2485-2515. doi: 10.1038/s44321-024-00130-1. Epub 2024 Sep 11.
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.
在脓毒症中，有限的食物摄入和能量消耗的增加会引起饥饿反应，但由于肝组织中 PPARα 的表达迅速下降，这种反应受到了损害，PPARα 是细胞内游离脂肪酸分解代谢所必需的转录因子。该 PPARα 下调的上游机制尚不清楚。我们发现，脓毒症导致 HNF4α 的进行性肝失活，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的致死率、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 激动剂在所有水平上都能对抗脓毒症，与细菌负荷无关，这表明 HNF4α 在对脓毒症的耐受中至关重要。总之，在脓毒症期间，肝脏 HNF4α 的活性降低，导致 PPARα 下调、代谢问题以及 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。
