Omics · study · 2026
CXCL6 exacerbates metabolic dysfunction-associated steatohepatitis by suppressing LPIN1-mediated fatty acid oxidation in hepatocytes
Listed in NCBI GEO
Progression of hepatic steatosis to metabolic dysfunction-associated steatohepatitis (MASH) involves impaired fatty acid (FA) oxidation, which causes lipotoxicity and inflammation in hepatocytes.
Description
MASH is characterized by upregulation of the neutrophil-recruiting chemokine CXCL6. Although hepatocytes produce CXCL6, its direct contribution to MASH progression in hepatocytes, beyond neutrophil recruitment, remains unclear.
Here, we show that Cxcl5, the murine homolog of human CXCL6, promotes steatosis-to-MASH transition when overexpressed in the mouse liver, whereas Cxcl5 deficiency protects against diet-induced MASH. Transcriptomic analysis of Cxcl5-deficient mice showed upregulation of FA metabolism genes. This is accompanied by reduced hepatic FA levels and increased Lipin-1 (LPIN1) expression, which activates PPARα.
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In vitro, recombinant mouse CXCL5 suppressed LPIN1 and PPARα expression in mouse hepatocytes, whereas Cxcl5-deficient hepatocytes exhibited elevated levels of both. Mechanistically, CXCL6 induced JNK activation, leading to inhibitory phosphorylation of the glucocorticoid receptor (GR). Luciferase assays demonstrated that CXCL6 attenuated GR-dependent LPIN1 promoter activation.
Lpin1 knockdown reversed the protective phenotype in Cxcl5-deficient mice, indicating that LPIN1 suppression is essential for CXCL6-driven MASH progression. Human MASH samples consistently exhibited reduced hepatic LPIN1 expression and an inverse correlation between LPIN1 and CXCL6 expression. In conclusion, CXCL6 drives MASH progression by inhibiting GR-mediated LPIN1 transactivation in hepatocytes, impairing FA oxidation and promoting lipotoxicity.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE325nnn/GSE325102 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE325102 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1438650 ncbi.nlm.nih.gov/bioproject/PRJNA1438650 ↗
project · from NCBI GEO
- PubMed 42212316 pubmed.ncbi.nlm.nih.gov/42212316 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Mus musculus
- From keywords
- Life Sciences
Provenance · 1 source records, 7 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE325102 | 12 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:10090 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |