LSR targets YAP to modulate intestinal Paneth cell differentiation

Area of Science:

• Cell Biology
• Gastroenterology
• Molecular Biology

Background:

• Lipolysis-stimulated lipoprotein receptor (LSR) is known for its roles in epithelial tight junctions and lipoprotein metabolism.
• Its function in intestinal epithelium homeostasis and disease remains largely unexplored.

Purpose of the Study:

• To investigate the role of LSR in intestinal epithelium homeostasis.
• To determine LSR's contribution to the pathogenesis of intestinal diseases, specifically necrotizing enterocolitis.

Main Methods:

• Conditional deletion mouse models and ex vivo organoid cultures were employed.
• Mechanistic studies involved assessing YAP protein levels, phosphorylation, and proteasomal degradation.
• Gain- and loss-of-function studies were conducted to evaluate LSR's impact on disease models.

Main Results:

• LSR elimination in intestinal stem cells led to the disappearance of Paneth cells.
• LSR deficiency increased YAP abundance by modulating its phosphorylation and proteasomal degradation.
• LSR protected against necrotizing enterocolitis by enhancing Paneth cell differentiation.

Conclusions:

• LSR is an essential factor for Paneth cell differentiation in the small intestinal epithelium.
• LSR acts as an upstream negative regulator of YAP activity.
• LSR represents a potential therapeutic target for necrotizing enterocolitis.