CXCL6 exacerbates metabolic dysfunction-associatedsteatohepatitis by suppressing LPIN1-mediated fatty acid oxidation in hepatocytes

초록

Progression of hepatic steatosis to metabolic dysfunction-associated steatohepatitis (MASH) is driven by impaired fatty acid (FA) oxidation and subsequent hepatocyte lipotoxicity. While MASH is characterizedby upregulation of the neutrophil chemoattractant CXCL6, which functions through CXCR2, the directimpact of this pathway on hepatocyte FA metabolism during MASH progression remains unclear. Here, we demonstrate that hepatic overexpression of Cxcl5 (the murine homolog of CXCL6) inhibits hepatocyteFA oxidation and promotes MASH progression in mice. In contrast,Cxcl5 deficiency conferredprotection against diet-induced MASH by reducing hepatic FA levels and restoring the expression of LPIN1, a transcriptional coactivator of PPAR alpha, thereby normalizing FA metabolic gene expression.Mechanistically, CXCL6 activated JNK, leading to the inhibitory phosphorylation of the glucocorticoidreceptor (GR). This blockade prevented GR-dependent activation of the LPIN1 promoter, therebysuppressing the LPIN1-PPAR alpha axis in hepatocytes.Lpin1 knockdown reversed the protective phenotypein Cxcl5-deficient mice, confirming that LPIN1 suppression is the essential driver of CXCL6-mediatedMASH progression. Consistently, human MASH samples exhibited reduced LPIN1 expression, whichinversely correlated with CXCL6 expression. In conclusion, beyond its canonical role in neutrophilrecruitment, CXCL6 promotes MASH progression by inhibiting the GR-LPIN1-PPAR alpha axis in hepatocytes, resulting in impaired FA oxidation and lipotoxicity.

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