Diosmetin alleviates TNFα-induced liver inflammation by improving liver sinusoidal endothelial cell dysfunction

Area of Science:

• Hepatology
• Immunology
• Pharmacology

Background:

• Sterile inflammation is a key driver in liver diseases like non-alcoholic fatty liver disease.
• Tumor necrosis factor alpha (TNFα) activates liver sinusoidal endothelial cells (LSEC), promoting liver inflammation.
• Reduced Mcpip1 expression is observed in obese patients with elevated TNFα, LSEC dysfunction, and liver inflammation.

Purpose of the Study:

• To create and validate a mouse model of LSEC dysfunction mirroring obese patients with high TNFα.
• To investigate diosmetin's potential as a therapeutic agent for liver inflammation by modulating LSEC dysfunction.

Main Methods:

• Generated Mcpip1 knock-out mice in myeloid cells (Mcpip1fl/flLysMCre) to model patient inflammation.
• Administered diosmetin to mice and assessed its effects on LSEC activation and liver inflammation in vitro and in vivo.
• Investigated the underlying mechanisms, including the NF-κB pathway.

Main Results:

• Mcpip1fl/flLysMCre mice exhibited systemic and liver inflammation consistent with patient observations.
• Diosmetin treatment significantly reduced TNFα-induced LSEC activation and liver inflammation in the mouse model.
• Diosmetin's anti-inflammatory effects in the liver were achieved without impacting systemic inflammation.

Conclusions:

• The Mcpip1fl/flLysMCre mouse model is a valuable tool for studying liver anti-inflammatory therapies.
• Diosmetin demonstrates significant anti-inflammatory properties in the liver by modulating LSEC dysfunction.
• Diosmetin shows potential as a supportive therapy for human liver inflammation.