LDL regulates intestinal stem cell homeostasis via PPAR pathway

Area of Science:

• Gastroenterology and Oncology
• Molecular Biology
• Metabolic Diseases

Background:

• Epidemiological studies link hyperlipidemia to increased gut cancer risk.
• Intestinal stem cells (ISCs) are the origin of gut tumorigenesis.
• The effect of hyperlipidemia on ISC homeostasis is not well understood.

Purpose of the Study:

• To investigate the impact of hyperlipidemia on intestinal stem cell (ISC) homeostasis.
• To elucidate the molecular mechanisms by which hyperlipidemia affects ISCs.
• To explore potential therapeutic targets for hyperlipidemia-associated gut tumorigenesis.

Main Methods:

• Utilized LDL receptor (Ldlr) deficient mice to induce hyperlipidemia in vivo.
• Treated intestinal organoids with LDL ex vivo to assess effects on ISC stemness and survival.
• Investigated the role of Peroxisome Proliferator-Activated Receptor (PPAR) pathways and their downstream targets (CPT1A, PDK4).

Main Results:

• Hyperlipidemia induced by Ldlr deficiency enhanced ISC proliferation in vivo.
• LDL treatment impaired organoid survival but increased ISC stemness ex vivo, indicated by spheroid formation and self-renewal.
• LDL activated PPAR pathways; inhibiting PPAR and its targets (CPT1A, PDK4) reversed LDL's effects on ISCs.

Conclusions:

• Hyperlipidemia significantly modulates intestinal stem cell (ISC) homeostasis.
• LDL-induced activation of PPAR pathways plays a key role in altering ISC behavior.
• Targeting PPAR pathways may offer a strategy to mitigate hyperlipidemia-driven gut tumorigenesis.