Abstract
Bone morphogenetic proteins (BMPs) participate in the energy metabolism. BMP receptor type 2 (BMPR2) is expressed in the liver. Whether BMPR2 is involved in the pathophysiology of nonalcoholic fatty liver disease (NAFLD) has not been studied. In this study, we analyzed the RNA-sequence data of several patient cohorts and found that BMPR2 expression decreases at the stages of advanced fibrosis. A mouse model featuring BMPR2 knockout demonstrate that BMPR2 knockout in the liver produces profibrotic effect upon long-term high-fat and high-fructose (HFF) diet challenge. BMP signaling promotes biosynthesis of unsaturated fatty acids, which is repressed under BMPR2 knockout condition. The most affected unsaturated fatty acid, palmitoleic acid (POA), is found to activate CD169 macrophages. Moreover, CD169 macrophages is revealed to have high levels of lysosomal enzyme along with matrix metalloproteinase 8, which degrades collagen and alleviates fibrosis. Our study demonstrates that BMPR2 influences over the progression of liver fibrosis induced by the HFF diet through fatty acid-regulated CD169 macrophages. POA-primed macrophages might be a potential therapeutic strategy for the treatment of liver fibrosis.
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Data availability
The raw data of RNA-sequence were deposited in GEO database (GSE317724, GSE317725). Published datasets were downloaded from GEO (GSE4845232, GSE21362131, GSE16752330). Source data underlying graphs can be obtained from Supplementary data 1. Unedited Western blot images were included as Supplementary Figs. 6 and 7. All other data are available upon request from authors: Dr. Shuwen Qian, E-mail: shuwenqian2013@163.com or shuwenqian@fudan.edu.cn.
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Acknowledgements
This work was financially supported by National Natural Science Foundation grant 82330023 and 92457301 to Q.-Q.T., 82470914 to S.Q., the Science and Technology Commission of Shanghai Municipality (STCSM) (23ZR1413300) to S.Q., and National Key R&D Program of Ministry of Science and Technology of China (2018YFA0800401) to Q.-Q.T. We thank Tianlu Feng (University of Rochester, USA) to do some tests using quantitative PCR and Western blots in the summer break of freshman year (2025).
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S.Q. designed and conducted the experiments, analyzed data, and wrote the manuscript. H.M. conducted the experiments. J.Z., Q.P., M.D., L.W., J.W., and D.H. participated in conducting the experiments. Y.L. and Y.T. reviewed the manuscript. W. X. offered critical advices. Q.T. directed the project and reviewed the manuscript.
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Ma, H., Zhong, J., Peng, Q. et al. Palmitoleic acid promoted by BMPR2 signaling primes CD169 macrophages and alleviates liver fibrosis. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09972-6
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DOI: https://doi.org/10.1038/s42003-026-09972-6
