Lipolysis-stimulated lipoprotein receptor (LSR) is a multi‐functional protein that is best known for its roles in assembly of epithelial tricellular tight junctions and hepatic clearance of lipoproteins. Here, we investigate the function of LSR in intestine biology. By using multiple conditional deletion mouse models and ex vivo cultured organoids, we find that LSR elimination in intestinal stem cells results in disappearance of Paneth cell without affecting the differentiation of other cell lineages. Mechanistic studies reveal that LSR deficiency increase abundance and nuclear localization of YAP by modulating its phosphorylation and proteasomal degradation. Intestinal LSR-deficient mice are susceptible to development of necrotizing enterocolitis. In addition, LSR can sense and interpret fatty acid signals derived from dietary lipids and transduce into inactivation of YAP. Thus, this study identifies LSR as an upstream negative regulator of YAP activity and part of the mechanism mediating connection between fat diet and YAP signaling in intestine.

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