Faculty, Staff and Student Publications
Publication Date
9-1-2024
Journal
Nature Metabolism
Abstract
Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 in a STAT3-dependent manner, leading to the efflux of bone marrow neutrophils to the circulation and damaged liver. Cholesterol, via its receptor ERRα, stimulates neutrophils to secrete hepatocyte growth factor to accelerate hepatocyte proliferation. Altogether, our findings reveal a LIFR-STAT3-CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-ERRα-hepatocyte growth factor axis that form bidirectional hepatocyte-neutrophil cross-talk to repair and regenerate the liver.
Keywords
Liver Regeneration, Animals, Hepatocytes, Mice, Cholesterol, Neutrophils, STAT3 Transcription Factor, Leukemia Inhibitory Factor Receptor alpha Subunit, Liver, Cell Proliferation, Hepatocyte Growth Factor, Chemokine CXCL1, Mice, Inbred C57BL
DOI
10.1038/s42255-024-01110-y
PMID
39147934
PMCID
PMC11498095
PubMedCentral® Posted Date
3-1-2025
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Bioinformatics Commons, Biomedical Informatics Commons, Endocrinology, Diabetes, and Metabolism Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons