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

ABSTRACT: Progression of hepatic steatosis to metabolic dysfunction-associated steatohepatitis (MASH) involves impaired fatty acid (FA) oxidation, which causes lipotoxicity and inflammation in hepatocytes. 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. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE325102 | GEO | 2026/06/03

REPOSITORIES: GEO

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Project description:Background: Studies in mice have shown that PPARα is an important regulator of lipid metabolism in liver and a key transcription factor involved in the adaptive response to fasting. However, much less is known about the role of PPARα in human liver. Here we set out to study the function of PPARα in human liver via analysis of whole genome gene regulation in human liver slices treated with the PPARα agonist Wy14643. Results: Quantitative PCR indicated that PPARα is well expressed in human liver and human liver slices and that the classical PPARα targets PLIN2, VLDLR, ANGPTL4, CPT1A and PDK4 are robustly induced by PPARα activation. Transcriptomics analysis indicated that 617 genes were upregulated and 665 genes were downregulated by PPARα activation (q value<0.05). Many genes induced by PPARα activation were involved in lipid metabolism (ACSL5, AGPAT9, FADS1, SLC27A4), xenobiotic metabolism (POR, ABCC2, CYP3A5) or the unfolded protein response, whereas most of the downregulated genes were involved in immune-related pathways. Among the most highly repressed genes upon PPARα activation were several chemokines (e.g. CXCL9-11, CCL8, CX3CL1, CXCL6), interferon γ-induced genes (e.g. IFITM1, IFIT1, IFIT2, IFIT3) and numerous other immune-related genes (e.g. TLR3, NOS2, and LCN2). Comparative analysis of gene regulation by Wy14643 between human liver slices and primary human hepatocytes showed that down-regulation of gene expression by PPARα is much better captured by liver slices as compared to primary hepatocytes. In particular, PPARα activation markedly suppressed immunity/inflammation-related genes in human liver slices but not in primary hepatocytes. Finally, several putative new target genes of PPARα were identified that were commonly induced by PPARα activation in the two human liver model systems, including TSKU, RHOF, CA12 and VSIG10L. Conclusion: Our manuscript demonstrates the suitability and superiority of human liver slices over primary hepatocytes for studying the functional role of PPARα in human liver. Our data underscore the major role of PPARα in regulation of hepatic lipid and xenobiotic metabolism in human liver and reveal a marked immuno-suppressive/anti-inflammatory effect of PPARα in human liver slices that may be therapeutically relevant for non-alcoholic fatty liver disease.

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

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