Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells
ABSTRACT The mechanism of exosomes derived from activated hepatic stellate cells (HSCs) involved in liver fibrosis is poorly understood. We previously reported that hypoxia‐inducible factor 1 (Hif‐1) regulated HSC activation, and, therefore, we investigated in current work whether Hif‐1 regulates ex...
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| creator | Wan, Lu Xia, Tian Du, Yanqin Liu, Jie Xie, Yuyu Zhang, Yijie Guan, Fei Wu, Jun Wang, Xiaochuan Shi, Chunwei |
| description | ABSTRACT
The mechanism of exosomes derived from activated hepatic stellate cells (HSCs) involved in liver fibrosis is poorly understood. We previously reported that hypoxia‐inducible factor 1 (Hif‐1) regulated HSC activation, and, therefore, we investigated in current work whether Hif‐1 regulates exosome secretion and the metabolic switch of HSCs, thus affecting the metabolism of liver nonparenchymal cells. In this study, the characteristics of exosomes from HSCs were assessed via electron microscopy, Western blot analysis, and acetylcholinesterase activity. Confocal microscopy was used to measure the uptake of exosomes by quiescent HSCs, Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs). Hif‐1α was inhibited via 2‐ME or specific small interfering RNAs to investigate its role in exosomes derived from HSCs. It was determined that glucose transporter 1 and pyruvate kinase M2 were increasingly expressed in fibrotic liver samples, cell lysates, and exosomes derived from activated HSCs. Exosomes released from HSCs were associated with activation and glucose uptake of HSCs. Delivery of exosomes from activated HSCs induced glycolysis of quiescent HSCs, KCs, and LSECs. Disruption of Hif‐1 expression suppressed the glycolysis effect delivered by exosomes. Conclusively, our results demonstrated that exosomes secreted by activated HSCs affect the metabolic switch of liver nonparenchymal cells via delivery of glycolysis‐related proteins. These findings represent a novel mechanism that contributes to liver fibrosis and has significant implications for new diagnosis and treatment of liver diseases.—Wan, L., Xia, T., Du, Y., Liu, J., Xie, Y., Zhang, Y., Guan, F., Wu, J., Wang, X., Shi, C. Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells. FASEB J. 33, 8530–8542 (2019). www.fasebj.org |
| doi_str_mv | 10.1096/fj.201802675R |
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The mechanism of exosomes derived from activated hepatic stellate cells (HSCs) involved in liver fibrosis is poorly understood. We previously reported that hypoxia‐inducible factor 1 (Hif‐1) regulated HSC activation, and, therefore, we investigated in current work whether Hif‐1 regulates exosome secretion and the metabolic switch of HSCs, thus affecting the metabolism of liver nonparenchymal cells. In this study, the characteristics of exosomes from HSCs were assessed via electron microscopy, Western blot analysis, and acetylcholinesterase activity. Confocal microscopy was used to measure the uptake of exosomes by quiescent HSCs, Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs). Hif‐1α was inhibited via 2‐ME or specific small interfering RNAs to investigate its role in exosomes derived from HSCs. It was determined that glucose transporter 1 and pyruvate kinase M2 were increasingly expressed in fibrotic liver samples, cell lysates, and exosomes derived from activated HSCs. Exosomes released from HSCs were associated with activation and glucose uptake of HSCs. Delivery of exosomes from activated HSCs induced glycolysis of quiescent HSCs, KCs, and LSECs. Disruption of Hif‐1 expression suppressed the glycolysis effect delivered by exosomes. Conclusively, our results demonstrated that exosomes secreted by activated HSCs affect the metabolic switch of liver nonparenchymal cells via delivery of glycolysis‐related proteins. These findings represent a novel mechanism that contributes to liver fibrosis and has significant implications for new diagnosis and treatment of liver diseases.—Wan, L., Xia, T., Du, Y., Liu, J., Xie, Y., Zhang, Y., Guan, F., Wu, J., Wang, X., Shi, C. Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells. FASEB J. 33, 8530–8542 (2019). www.fasebj.org</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.201802675R</identifier><identifier>PMID: 30970216</identifier><language>eng</language><publisher>United States: Federation of American Societies for Experimental Biology</publisher><subject>Animals ; Cell Line ; Endothelial Cells - metabolism ; Exosomes - metabolism ; Glucose Transporter Type 1 - metabolism ; glycolysis ; Glycolysis - physiology ; hepatic fibrosis ; Hepatic Stellate Cells - metabolism ; Hepatocytes - metabolism ; Hif-1 ; Humans ; Kupffer Cells - metabolism ; Liver - metabolism ; Liver Cirrhosis - metabolism ; Mice ; Mice, Inbred BALB C ; Pyruvate Kinase - metabolism ; Signal Transduction - physiology</subject><ispartof>The FASEB journal, 2019-07, Vol.33 (7), p.8530-8542</ispartof><rights>FASEB</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455R-80847c0ec2ce281eb5dbcbecc1f0b3bd3c545b943b5c111c9c1aeed21f3e1853</citedby><cites>FETCH-LOGICAL-c455R-80847c0ec2ce281eb5dbcbecc1f0b3bd3c545b943b5c111c9c1aeed21f3e1853</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.201802675R$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.201802675R$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30970216$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wan, Lu</creatorcontrib><creatorcontrib>Xia, Tian</creatorcontrib><creatorcontrib>Du, Yanqin</creatorcontrib><creatorcontrib>Liu, Jie</creatorcontrib><creatorcontrib>Xie, Yuyu</creatorcontrib><creatorcontrib>Zhang, Yijie</creatorcontrib><creatorcontrib>Guan, Fei</creatorcontrib><creatorcontrib>Wu, Jun</creatorcontrib><creatorcontrib>Wang, Xiaochuan</creatorcontrib><creatorcontrib>Shi, Chunwei</creatorcontrib><title>Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>ABSTRACT
The mechanism of exosomes derived from activated hepatic stellate cells (HSCs) involved in liver fibrosis is poorly understood. We previously reported that hypoxia‐inducible factor 1 (Hif‐1) regulated HSC activation, and, therefore, we investigated in current work whether Hif‐1 regulates exosome secretion and the metabolic switch of HSCs, thus affecting the metabolism of liver nonparenchymal cells. In this study, the characteristics of exosomes from HSCs were assessed via electron microscopy, Western blot analysis, and acetylcholinesterase activity. Confocal microscopy was used to measure the uptake of exosomes by quiescent HSCs, Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs). Hif‐1α was inhibited via 2‐ME or specific small interfering RNAs to investigate its role in exosomes derived from HSCs. It was determined that glucose transporter 1 and pyruvate kinase M2 were increasingly expressed in fibrotic liver samples, cell lysates, and exosomes derived from activated HSCs. Exosomes released from HSCs were associated with activation and glucose uptake of HSCs. Delivery of exosomes from activated HSCs induced glycolysis of quiescent HSCs, KCs, and LSECs. Disruption of Hif‐1 expression suppressed the glycolysis effect delivered by exosomes. Conclusively, our results demonstrated that exosomes secreted by activated HSCs affect the metabolic switch of liver nonparenchymal cells via delivery of glycolysis‐related proteins. These findings represent a novel mechanism that contributes to liver fibrosis and has significant implications for new diagnosis and treatment of liver diseases.—Wan, L., Xia, T., Du, Y., Liu, J., Xie, Y., Zhang, Y., Guan, F., Wu, J., Wang, X., Shi, C. Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells. FASEB J. 33, 8530–8542 (2019). www.fasebj.org</description><subject>Animals</subject><subject>Cell Line</subject><subject>Endothelial Cells - metabolism</subject><subject>Exosomes - metabolism</subject><subject>Glucose Transporter Type 1 - metabolism</subject><subject>glycolysis</subject><subject>Glycolysis - physiology</subject><subject>hepatic fibrosis</subject><subject>Hepatic Stellate Cells - metabolism</subject><subject>Hepatocytes - metabolism</subject><subject>Hif-1</subject><subject>Humans</subject><subject>Kupffer Cells - metabolism</subject><subject>Liver - metabolism</subject><subject>Liver Cirrhosis - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Pyruvate Kinase - metabolism</subject><subject>Signal Transduction - physiology</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE9vEzEQRy0EoqFw5Ip85LLtjB3vHzhB1ZRCEKiE88qeHSsb7a6DvWnJd-BDs1Fa4MTpJ42enkZPiJcIZwhVfu43ZwqwBJUX5uaRmKHRkOVlDo_FDMpKZXmuyxPxLKUNACBg_lScaKgKUJjPxK_LnyGFnpP0MfTS0tje2pEbueatHVuSaeSumy6Spk2SwjDadpBXy-8rlHZo5NdPn9UbaWUMHUsfouQH44T1PFoXuoPnrh1pLYOXXXvLUQ5h2NrIA633ve2O9ufiibdd4hf3eypWi8vVxYds-eXq-uLdMqO5MTdZCeW8IGBSxKpEdqZx5JgIPTjtGk1mblw1184QIlJFaJkbhV4zlkafitdH7TaGHztOY9236fCAHTjsUq0UFJUuCq0nNDuiFENKkX29jW1v475GqA_9a7-p__af-Ff36p3ruflDPwSfgLdH4K7teP9_W7349l4tPv6j_w2MUZRX</recordid><startdate>201907</startdate><enddate>201907</enddate><creator>Wan, Lu</creator><creator>Xia, Tian</creator><creator>Du, Yanqin</creator><creator>Liu, Jie</creator><creator>Xie, Yuyu</creator><creator>Zhang, Yijie</creator><creator>Guan, Fei</creator><creator>Wu, Jun</creator><creator>Wang, Xiaochuan</creator><creator>Shi, Chunwei</creator><general>Federation of American Societies for Experimental Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201907</creationdate><title>Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells</title><author>Wan, Lu ; Xia, Tian ; Du, Yanqin ; Liu, Jie ; Xie, Yuyu ; Zhang, Yijie ; Guan, Fei ; Wu, Jun ; Wang, Xiaochuan ; Shi, Chunwei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455R-80847c0ec2ce281eb5dbcbecc1f0b3bd3c545b943b5c111c9c1aeed21f3e1853</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Cell Line</topic><topic>Endothelial Cells - metabolism</topic><topic>Exosomes - metabolism</topic><topic>Glucose Transporter Type 1 - metabolism</topic><topic>glycolysis</topic><topic>Glycolysis - physiology</topic><topic>hepatic fibrosis</topic><topic>Hepatic Stellate Cells - metabolism</topic><topic>Hepatocytes - metabolism</topic><topic>Hif-1</topic><topic>Humans</topic><topic>Kupffer Cells - metabolism</topic><topic>Liver - metabolism</topic><topic>Liver Cirrhosis - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Pyruvate Kinase - metabolism</topic><topic>Signal Transduction - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wan, Lu</creatorcontrib><creatorcontrib>Xia, Tian</creatorcontrib><creatorcontrib>Du, Yanqin</creatorcontrib><creatorcontrib>Liu, Jie</creatorcontrib><creatorcontrib>Xie, Yuyu</creatorcontrib><creatorcontrib>Zhang, Yijie</creatorcontrib><creatorcontrib>Guan, Fei</creatorcontrib><creatorcontrib>Wu, Jun</creatorcontrib><creatorcontrib>Wang, Xiaochuan</creatorcontrib><creatorcontrib>Shi, Chunwei</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wan, Lu</au><au>Xia, Tian</au><au>Du, Yanqin</au><au>Liu, Jie</au><au>Xie, Yuyu</au><au>Zhang, Yijie</au><au>Guan, Fei</au><au>Wu, Jun</au><au>Wang, Xiaochuan</au><au>Shi, Chunwei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2019-07</date><risdate>2019</risdate><volume>33</volume><issue>7</issue><spage>8530</spage><epage>8542</epage><pages>8530-8542</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>ABSTRACT
The mechanism of exosomes derived from activated hepatic stellate cells (HSCs) involved in liver fibrosis is poorly understood. We previously reported that hypoxia‐inducible factor 1 (Hif‐1) regulated HSC activation, and, therefore, we investigated in current work whether Hif‐1 regulates exosome secretion and the metabolic switch of HSCs, thus affecting the metabolism of liver nonparenchymal cells. In this study, the characteristics of exosomes from HSCs were assessed via electron microscopy, Western blot analysis, and acetylcholinesterase activity. Confocal microscopy was used to measure the uptake of exosomes by quiescent HSCs, Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs). Hif‐1α was inhibited via 2‐ME or specific small interfering RNAs to investigate its role in exosomes derived from HSCs. It was determined that glucose transporter 1 and pyruvate kinase M2 were increasingly expressed in fibrotic liver samples, cell lysates, and exosomes derived from activated HSCs. Exosomes released from HSCs were associated with activation and glucose uptake of HSCs. Delivery of exosomes from activated HSCs induced glycolysis of quiescent HSCs, KCs, and LSECs. Disruption of Hif‐1 expression suppressed the glycolysis effect delivered by exosomes. Conclusively, our results demonstrated that exosomes secreted by activated HSCs affect the metabolic switch of liver nonparenchymal cells via delivery of glycolysis‐related proteins. These findings represent a novel mechanism that contributes to liver fibrosis and has significant implications for new diagnosis and treatment of liver diseases.—Wan, L., Xia, T., Du, Y., Liu, J., Xie, Y., Zhang, Y., Guan, F., Wu, J., Wang, X., Shi, C. Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells. FASEB J. 33, 8530–8542 (2019). www.fasebj.org</abstract><cop>United States</cop><pub>Federation of American Societies for Experimental Biology</pub><pmid>30970216</pmid><doi>10.1096/fj.201802675R</doi><tpages>13</tpages></addata></record> |
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| subjects | Animals Cell Line Endothelial Cells - metabolism Exosomes - metabolism Glucose Transporter Type 1 - metabolism glycolysis Glycolysis - physiology hepatic fibrosis Hepatic Stellate Cells - metabolism Hepatocytes - metabolism Hif-1 Humans Kupffer Cells - metabolism Liver - metabolism Liver Cirrhosis - metabolism Mice Mice, Inbred BALB C Pyruvate Kinase - metabolism Signal Transduction - physiology |
| title | Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells |
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