TY - JOUR
T1 - Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis
AU - Khanal, Shalil
AU - Liu, Yuanhang
AU - Bamidele, Adebowale O.
AU - Wixom, Alexander Q.
AU - Washington, Alexander M.
AU - Jalan-Sakrikar, Nidhi
AU - Cooper, Shawna A.
AU - Vuckovic, Ivan
AU - Zhang, Song
AU - Zhong, Jun
AU - Johnson, Kenneth L.
AU - Charlesworth, M. Cristine
AU - Kim, Iljung
AU - Yeon, Yubin
AU - Yoon, Sangwoong
AU - Noh, Yung Kyun
AU - Meroueh, Chady
AU - Timbilla, Abdul Aziz
AU - Yaqoob, Usman
AU - Gao, Jinhang
AU - Kim, Yohan
AU - Lucien, Fabrice
AU - Huebert, Robert C.
AU - Hay, Nissim
AU - Simons, Michael
AU - Shah, Vijay H.
AU - Kostallari, Enis
N1 - Publisher Copyright:
Copyright © 2024 The Authors, some rights reserved;
PY - 2024/6/28
Y1 - 2024/6/28
N2 - Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation of EV-related pathways in the liver pericentral zone, which was abrogated by glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs up-regulated the expression of EV-related genes such as Ras-related protein Rab-31 (RAB31) by enhancing histone 3 lysine 9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.
AB - Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation of EV-related pathways in the liver pericentral zone, which was abrogated by glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs up-regulated the expression of EV-related genes such as Ras-related protein Rab-31 (RAB31) by enhancing histone 3 lysine 9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.
UR - http://www.scopus.com/inward/record.url?scp=85197108628&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85197108628&partnerID=8YFLogxK
U2 - 10.1126/sciadv.adn5228
DO - 10.1126/sciadv.adn5228
M3 - Article
C2 - 38941469
AN - SCOPUS:85197108628
SN - 2375-2548
VL - 10
JO - Science Advances
JF - Science Advances
IS - 26
M1 - eadn5228
ER -