PPARγ alleviated hepatocyte steatosis through reducing SOCS3 by inhibiting JAK2/STAT3 pathway

Area of Science:

• Hepatology
• Molecular Biology
• Immunology

Background:

• Insulin resistance (IR) is central to non-alcoholic fatty liver disease (NAFLD) pathogenesis.
• Both Peroxisome proliferator-activated receptor gamma (PPARγ) and suppressor of cytokine signaling 3 (SOCS3) are implicated in NAFLD-related IR.
• The interaction between PPARγ, SOCS3, and hepatic steatosis regulation remains unclear.

Purpose of the Study:

• To investigate the interplay between PPARγ and SOCS3 in regulating hepatic steatosis in NAFLD.
• To elucidate the molecular mechanisms involving the JAK2/STAT3 pathway.

Main Methods:

• Kuppfer cells (KCs) were treated with lipopolysaccharide (LPS) to induce dysfunction.
• BRL-3A hepatocytes were treated with palmitic acid and KC-conditioned medium (KCCM).
• The effects of PPARγ agonist (rosiglitazone, ROZ) and JAK2 inhibitor (AG490) on SOCS3, JAK2, and STAT3 expression were analyzed.

Main Results:

• LPS treatment impaired KC phagocytosis while increasing TNF-α and IL-6 release.
• KCCM treatment significantly increased SOCS3, JAK2, and STAT3 mRNA and protein levels in steatotic hepatocytes.
• AG490 or ROZ treatment inhibited these KCCM-induced increases, indicating suppression of the JAK2/STAT3 pathway.
• ROZ alleviated steatosis by reducing SOCS3 expression.

Conclusions:

• KC dysfunction contributes to hepatocyte steatosis by promoting SOCS3 expression.
• PPARγ activation (ROZ) ameliorates hepatic steatosis by inhibiting SOCS3 expression through the JAK2/STAT3 pathway.