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| Status |
Public on Oct 31, 2023 |
| Title |
A critical role for Hepatocyte Nuclear Factor 4 alpha in polymicrobial sepsis-associated metabolic reprogramming and death: ATAC-seq after CLP sepsis model |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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.
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| 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
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| Contributor(s) |
Van Dender C, Timmermans S, Paakinaho V, Vanderhaeghen T, Vandewalle J, Claes M, Roman B, De Waele J, Croubels S, De Bosscher K, Palvimo J, Libert C |
| Citation(s) |
39261648 |
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| Submission date |
Oct 06, 2023 |
| Last update date |
Nov 21, 2024 |
| Contact name |
Steven Timmermans |
| Organization name |
VIB-UGent
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| Street address |
Technologiepark 71
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| City |
Gent |
| ZIP/Postal code |
9052 |
| Country |
Belgium |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA1024961 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE244821_RAW.tar |
1.0 Gb |
(http)(custom) |
TAR (of BW, NARROWPEAK) |
SRA Run Selector |
| Raw data are available in SRA |
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