Phospholipid Remodeling and Cholesterol Availability Regulate Intestinal Stemness and Tumorigenesis

Area of Science:

• Cell Biology
• Gastroenterology
• Oncology

Background:

• Cellular proliferation requires adequate building blocks like lipids.
• Excess dietary lipids are associated with increased cancer risk.
• The precise regulation of intestinal stem cell (ISC) proliferation by membrane composition and tumorigenesis remains unclear.

Purpose of the Study:

• To investigate the link between membrane phospholipid remodeling, cholesterol biosynthesis, and ISC proliferation.
• To determine the role of cholesterol in ISC proliferation and intestinal tumorigenesis.

Main Methods:

• Studied the effects of inhibiting the phospholipid-remodeling enzyme Lpcat3 on membrane saturation and cholesterol biosynthesis.
• Assessed ISC proliferation in Lpcat3-deficient organoids and mice.
• Investigated the impact of pharmacologic cholesterol synthesis inhibition.
• Examined the effects of increased cellular cholesterol content and dietary cholesterol.
• Analyzed tumor formation in Apcmin mice with disrupted Lpcat3-dependent homeostasis.

Main Results:

• Inhibition of Lpcat3 increases membrane saturation and stimulates cholesterol biosynthesis, driving ISC proliferation.
• Pharmacologic inhibition of cholesterol synthesis normalizes hyperproliferation in Lpcat3-deficient models.
• Increased cellular cholesterol or dietary cholesterol promotes ISC proliferation in vivo.
• Disruption of phospholipid and cholesterol homeostasis enhances tumor formation in Apcmin mice.

Conclusions:

• Cholesterol acts as a mitogen for ISCs, linking membrane phospholipid remodeling to ISC proliferation.
• A critical dietary-responsive phospholipid-cholesterol axis regulates ISC proliferation and intestinal tumorigenesis.