Intestinal Sirtuin 1 Controls Liver Regeneration via Regulating the Intestinal Farnesoid X Receptor/Fibroblast Growth...

Area of Science:

• Hepatology
• Gastroenterology
• Molecular Biology

Background:

• The gut-liver axis plays a vital role in liver regeneration, but its mechanisms are not fully understood.
• Intestinal Sirtuin-1 (SIRT1) involvement in liver regeneration requires further investigation.
• Understanding these processes is key for developing therapies for liver diseases and transplantation.

Purpose of the Study:

• To define the role of intestinal Sirtuin-1 (SIRT1) in mouse liver regeneration.
• To investigate the molecular mechanisms linking intestinal SIRT1 to liver repair.

Main Methods:

• Partial hepatectomy (PHx) was performed on intestinal-specific SIRT1 knockout (SIRT^intKO) and wild-type (WT) mice.
• Immunostaining, immunoblotting, and bulk RNA sequencing were used to analyze liver and intestinal tissues.
• Key proteins like Farnesoid X receptor (FXR) and Fibroblast Growth Factor-15 (FGF15) were assessed.

Main Results:

• SIRT^intKO mice showed reduced hepatocyte proliferation, increased senescence, and bile acid accumulation.
• Despite initial damage, SIRT^intKO mice restored liver mass, activating liver progenitor cells.
• Impaired proliferation in KO mice correlated with STAT pathway downregulation and altered metabolism; intestinal FXR/FGF15 expression was reduced.

Conclusions:

• Intestinal SIRT1 is essential for effective liver regeneration post-PHx.
• SIRT1 regulates liver regeneration via upstream control of the intestinal FXR/FGF15 axis.
• Targeting intestinal SIRT1 or the FXR/FGF15 pathway may offer therapeutic potential for liver regeneration.