Cysteine cathepsins control hepatic NF-κB-dependent inflammation via sirtuin-1 regulation

Area of Science:

• Biochemistry
• Molecular Biology
• Hepatology

Background:

• Sirtuin-1 (SIRT1) is crucial for regulating hepatic metabolism.
• The role of SIRT1 in NF-κB-dependent liver inflammation is not well understood.
• Cysteine cathepsins (CTSB/S) degrade proteins and target SIRT1.

Purpose of the Study:

• To investigate the roles of CTSB/S and SIRT1 in regulating hepatic inflammation.
• To explore the therapeutic potential of targeting CTSB/S for liver inflammation.

Main Methods:

• Utilized primary hepatic cells (parenchymal and non-parenchymal) and cell lines.
• Employed a dietary mouse model of non-alcoholic steatohepatitis (NASH).
• Administered LPS or TNF to induce inflammation in vivo and in vitro.

Main Results:

• CTSB/S inhibition decreased nuclear p65-NF-κB and inflammatory gene expression via enhanced SIRT1.
• SIRT1 silencing increased inflammatory gene expression.
• In NASH models and LPS-challenged mice, cathepsins and NF-κB were activated.
• Cysteine cathepsin inhibition reduced NF-κB-dependent hepatic inflammation by regulating SIRT1.

Conclusions:

• CTSB/S play a significant role in regulating hepatic inflammation.
• Targeting cysteine cathepsins represents a novel therapeutic strategy for liver diseases.
• The CTSB/S-SIRT1 axis is a key regulator of NF-κB-dependent hepatic inflammation.