Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ.

Area of Science:

• Hepatology
• Pharmacology
• Molecular Biology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), are significant health concerns.
• Elafibranor, a dual peroxisome proliferator-activated receptor (PPAR)α and β/δ agonist, is in phase III trials for MASLD.
• Choline-deficient high-fat diet (CD-HFD) fed mice serve as a relevant model for MASH, exhibiting obesity and insulin resistance.

Purpose of the Study:

• To investigate the therapeutic effects of elafibranor in a mouse model of MASH.
• To elucidate the molecular mechanisms underlying elafibranor's action, particularly its impact on hepatic pathways.

Main Methods:

• Administration of elafibranor to mice fed a CD-HFD.
• Assessment of liver steatosis, inflammation, and fibrosis.
• Analysis of epithelial-mesenchymal transition (EMT) markers and related proteins (S100A4, ASB2).
• In vitro studies using BRL-3A rat liver cells and primary mouse hepatocytes.

Main Results:

• Elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in CD-HFD mice.
• Unexpectedly, elafibranor increased S100A4 protein levels, a known promoter of EMT, through PPARβ/δ activation.
• This elafibranor-induced S100A4 increase was linked to altered EMT markers and reduced levels of ASB2, a protein that degrades S100A4.

Conclusions:

• Elafibranor demonstrates therapeutic potential for MASH by reducing liver damage.
• A novel finding is elafibranor's ability to increase hepatic S100A4 and promote EMT via PPARβ/δ.
• These results highlight a complex molecular effect of elafibranor beyond its anti-inflammatory and anti-steatotic properties.