Gut-liver axis calibrates intestinal stem cell fitness.

Publisher: Cell Press Country of Publication: United States NLM ID: 0413066 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4172 (Electronic) Linking ISSN: 00928674 NLM ISO Abbreviation: Cell Subsets: MEDLINE

Publication: Cambridge, Ma : Cell Press
Original Publication: Cambridge, MIT Press.

Liver*/metabolism ; Intestines*/cytology ; Intestines*/metabolism; Animals ; Mice ; Cell Proliferation ; PPAR alpha/metabolism ; Proteomics ; Stem Cells/metabolism ; Wnt Signaling Pathway

The gut and liver are recognized to mutually communicate through the biliary tract, portal vein, and systemic circulation. However, it remains unclear how this gut-liver axis regulates intestinal physiology. Through hepatectomy and transcriptomic and proteomic profiling, we identified pigment epithelium-derived factor (PEDF), a liver-derived soluble Wnt inhibitor, which restrains intestinal stem cell (ISC) hyperproliferation to maintain gut homeostasis by suppressing the Wnt/β-catenin signaling pathway. Furthermore, we found that microbial danger signals resulting from intestinal inflammation can be sensed by the liver, leading to the repression of PEDF production through peroxisome proliferator-activated receptor-α (PPARα). This repression liberates ISC proliferation to accelerate tissue repair in the gut. Additionally, treating mice with fenofibrate, a clinical PPARα agonist used for hypolipidemia, enhances colitis susceptibility due to PEDF activity. Therefore, we have identified a distinct role for PEDF in calibrating ISC expansion for intestinal homeostasis through reciprocal interactions between the gut and liver.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2024 Elsevier Inc. All rights reserved.)

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ZIA BC012034 United States ImNIH Intramural NIH HHS; ZIA DE000751 United States ImNIH Intramural NIH HHS

Keywords: PEDF; PPARα; Wnt/β-catenin signal; fenofibrate; gut-liver axis; intestinal stem cells

0 (PPAR alpha)

Date Created: 20240127 Date Completed: 20240221 Latest Revision: 20240310

20240310

PMC10923069

10.1016/j.cell.2024.01.001

38280375