{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:31:43Z","timestamp":1792503103005,"version":"4.5.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T00:00:00Z","timestamp":1601251200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T00:00:00Z","timestamp":1601251200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Liver fibrosis (LF) is a central pathological process that occurs in most types of chronic liver diseases. Advanced LF causes cirrhosis, hepatocellular carcinoma, and liver failure. However, the exact molecular mechanisms underlying the initiation and progression of LF remain largely unknown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>This study was designed to investigate the role of protein kinase D3 (PKD3; gene name <jats:italic toggle=\"yes\">Prkd3<\/jats:italic>) in the regulation of liver homeostasis. We generated global <jats:italic toggle=\"yes\">Prkd3<\/jats:italic> knockout (<jats:italic toggle=\"yes\">Prkd3\u2212\/\u2212\n                                 <\/jats:italic>) mice and myeloid\u2010cell\u2013specific <jats:italic toggle=\"yes\">Prkd3<\/jats:italic> knockout (<jats:italic toggle=\"yes\">Prkd3<\/jats:italic>\n                                 <jats:sup>\u2206LysM<\/jats:sup>) mice, and we found that both <jats:italic toggle=\"yes\">Prkd3\u2212\/\u2212\n                                 <\/jats:italic> mice and <jats:italic toggle=\"yes\">Prkd3\u2206LysM\n                                 <\/jats:italic> mice displayed spontaneous LF. PKD3 deficiency also aggravated CCl<jats:sub>4<\/jats:sub>\u2010induced LF. PKD3 is highly expressed in hepatic macrophages (HMs), and PKD3 deficiency skewed macrophage polarization toward a profibrotic phenotype. Activated profibrotic macrophages produced transforming growth factor beta that, in turn, activates hepatic stellate cells to become matrix\u2010producing myofibroblasts. Moreover, PKD3 deficiency decreased the phosphatase activity of SH2\u2010containing protein tyrosine phosphatase\u20101 (a bona\u2010fide PKD3 substrate), resulting in sustained signal transducer and activator of transcription 6 activation in macrophages. In addition, we observed that PKD3 expression in HMs was down\u2010regulated in cirrhotic human liver tissues.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>PKD3 deletion in mice drives LF through the profibrotic macrophage activation.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31176","type":"journal-article","created":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T06:20:20Z","timestamp":1581488420000},"page":"1717-1734","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":37,"title":["Deletion of Protein Kinase D3 Promotes Liver Fibrosis in Mice"],"prefix":"10.1097","volume":"72","author":[{"given":"Shuya","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Medicine,Aab Cardiovascular Research Institute,University of Rochester School of Medicine and Dentistry,Rochester,NY"},{"name":"Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education,Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Ningxia Medical University,Yinchuan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2676-6982","authenticated-orcid":false,"given":"Huan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine,Aab Cardiovascular Research Institute,University of Rochester School of Medicine and Dentistry,Rochester,NY"},{"name":"Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education,Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Ningxia Medical University,Yinchuan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meimei","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Medicine,Aab Cardiovascular Research Institute,University of Rochester School of Medicine and Dentistry,Rochester,NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuying","family":"Pei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education,Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Ningxia Medical University,Yinchuan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Hausser","sequence":"additional","affiliation":[{"name":"Institute of Cell Biology and Immunology,University of Stuttgart,Stuttgart,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eri","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Department of Molecular Immunology,Research Institute for Microbial Diseases,Osaka University,Osaka,Japan"},{"name":"Molecular Immunology,Immunology Frontier Research Center,Osaka University,Osaka,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Yamasaki","sequence":"additional","affiliation":[{"name":"Department of Molecular Immunology,Research Institute for Microbial Diseases,Osaka University,Osaka,Japan"},{"name":"Molecular Immunology,Immunology Frontier Research Center,Osaka University,Osaka,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8367-5526","authenticated-orcid":false,"given":"Zheng Gen","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Medicine,Aab Cardiovascular Research Institute,University of Rochester School of Medicine and Dentistry,Rochester,NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2020,9,28]]},"reference":[{"key":"hep31176-bib-0001-20241017","first-page":"435","article-title":"Liver fibrosis: direct antifibrotic agents and targeted 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