Low-density Lipoprotein Regulates Intestinal Stem Cell Homeostasis via PPAR Pathway

Epidemiological studies have highlighted a strong association between hyperlipidemia and an increased risk of cancer in the gut. Intestinal stem cells (ISCs) have been demonstrated as the cells of origin for tumorigenesis in the gut. However, the impact of hyperlipidemia on ISC homeostasis remains unclear. Here, we show that hyperlipidemia induced by low-density lipoprotein receptor (Ldlr) deficiency enhances ISC proliferation in vivo. Additionally, LDL treatment impairs organoid survival but increases ISC stemness ex vivo, as evidenced by the formation of poorly differentiated spheroid and higher ISC self-renewal capacity. Mechanistically, LDL treatment activates PPAR pathways, and pharmacological inhibition of PPAR and its downstream targets, including CPT1A and PDK4, mitigates the effect of LDL on ISCs. Furthermore, although Ldlr-/- intestines exhibit increased susceptibility to irradiation-induced crypt damage, they regenerate completely within a similar timeframe as controls. These findings demonstrate that hyperlipidemia modulates ISC homeostasis, providing new insights into the mechanism linking hyperlipidemia with tumorigenesis in the gut. Overall design: To evaluate the effect of LDL in intestineal stem cell ex vivo, duodenum and jejunum crypts from 3 mice were isolated and cultured as organoids for 5 days. Organoids were either treated with low density lipoprotein (LDL) or PBS control. Three biological replicates were analyzed for each of 2 treatment conditions