{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:31:46Z","timestamp":1792009906284,"version":"4.4.0"},"reference-count":29,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,2,6]],"date-time":"2020-02-06T00:00:00Z","timestamp":1580947200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81272436"],"award-info":[{"award-number":["81272436"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81572356"],"award-info":[{"award-number":["81572356"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81871997"],"award-info":[{"award-number":["81871997"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81470857"],"award-info":[{"award-number":["81470857"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002367","name":"Chinese Academy of Sciences","doi-asserted-by":"publisher","award":["XDB27020201"],"award-info":[{"award-number":["XDB27020201"]}],"id":[{"id":"10.13039\/501100002367","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R37AA010154"],"award-info":[{"award-number":["5R37AA010154"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R01DK077794"],"award-info":[{"award-number":["5R01DK077794"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and aims<\/jats:title><jats:p>Treatment of non\u2010alcoholic steatohepatitis (NASH) is challenging, because suppressing fibrotic progression has not been achieved consistently by drug candidates currently in clinical trials. The aim of this study was to investigate the molecular interplays underlying NASH\u2010associated fibrosis in a mouse NASH model and human specimens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mice were divided into 4 groups: Controls; NASH (high fat\/Calorie diet plus high fructose and glucose in drinking water, HFCD\u2010HF\/G) for 16\u00a0weeks; HFCD\u2010HF\/G plus docosahexaenoic acid (DHA) for 16 or 8\u00a0weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Along with NASH progression, fibrotic deposition was documented in HFCD\u2010HF\/G\u2010fed mice. Liver succinate content was significantly increased along with decreased expression of succinate dehydrogenase\u2010A (SDH\u2010A) in these mice; whereas, GPR\u201091 receptor expression was much enhanced in histology compared to control mice, and co\u2010localized histologically with hepatic stellate cells (HSCs). Succinate content was increased in fatty acid\u2010overloaded primary hepatocytes with significant oxidant stress and lipotoxicity. Exposure to succinate led to up\u2010regulation of GPR\u201091 receptor in primary and immortalized HSCs. In contrast, suppression of GPR\u201091 receptor expression abolished succinate stimulatory role in GPR\u201091 expression and extracellular matrix production in HSCs. All these changes were minimized or abrogated by DHA supplementation in vivo or in vitro. Moreover, GPR\u201091 receptor expression correlates with severity of fibrosis in human NASH biopsy specimens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Succinate accumulation in steatotoic hepatocytes may result in HSC activation through GPR\u201091 receptor signalling in NASH progression, and the cross\u2010talk between hepatocytes and HSC through GPR\u201091 signalling is most likely to be the molecular basis of fibrogenesis in NASH.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.14370","type":"journal-article","created":{"date-parts":[[2020,1,6]],"date-time":"2020-01-06T09:08:30Z","timestamp":1578301710000},"page":"830-843","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Succinate\u2010GPR\u201091 receptor signalling is responsible for nonalcoholic steatohepatitis\u2010associated fibrosis: Effects of DHA supplementation"],"prefix":"10.1111","volume":"40","author":[{"given":"Xue\u2010Jing","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology MOE\/NHC\/CAMS Key Laboratory of Medical Molecular Virology School of Basic Medical Sciences Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology MOE\/NHC\/CAMS Key Laboratory of Medical Molecular Virology School of Basic Medical Sciences Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo","family":"Du","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Duke University Medical Center Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology MOE\/NHC\/CAMS Key Laboratory of Medical Molecular Virology School of Basic Medical Sciences Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning\u2010Ping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Liver Diseases Fudan University Shanghai Medical College Shanghai China"},{"name":"Dept. of Gastroenterology &amp; Hepatology Zhongshan Hospital Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen\u2010Jian","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology MOE\/NHC\/CAMS Key Laboratory of Medical Molecular Virology School of Basic Medical Sciences Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Duke University Medical Center Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal F.","family":"Abdelmalek","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Duke University Medical Center Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen\u2010Yue","family":"Dong","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Plant Physiology and Ecology Shanghai Institutes of Biologic Sciences (SIBS) Chinese Academy of Sciences Shanghai China"},{"name":"University of Chinese Academy of Science Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiu\u2010Ping","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology School of Basic Medical Sciences Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology MOE\/NHC\/CAMS Key Laboratory of Medical Molecular Virology School of Basic Medical Sciences Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Yang","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Plant Physiology and Ecology Shanghai Institutes of Biologic Sciences (SIBS) Chinese Academy of Sciences Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Mae","family":"Diehl","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Duke University Medical Center Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9933-7364","authenticated-orcid":false,"given":"Jian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology MOE\/NHC\/CAMS Key Laboratory of Medical Molecular Virology School of Basic Medical Sciences Fudan University Shanghai China"},{"name":"Shanghai Institute of Liver Diseases Fudan University Shanghai Medical College Shanghai China"},{"name":"Dept. of Gastroenterology &amp; Hepatology Zhongshan Hospital Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,2,6]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1503519"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0104-9"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.06.003"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.07.027"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8641"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(16)30018-8"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.01.038"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61933-4"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29477"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29514"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/1756284818811508"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408398.2018.1425978"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27289"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1139\/apnm-2016-0689"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41374-018-0074-z"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2017.03.012"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(99)70406-3"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21093"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20701"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.12.022"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41374-018-0177-6"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v23.i15.2685"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.01.106"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2015.06.023"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jff.2015.11.028"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0907929"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28899"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clnu.2017.01.006"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.3109\/10408363.2015.1092106"}],"container-title":["Liver International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fliv.14370","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.14370","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/liv.14370","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.14370","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T01:25:28Z","timestamp":1694049928000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/liv.14370"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,6]]},"references-count":29,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,4]]}},"alternative-id":["10.1111\/liv.14370"],"URL":"https:\/\/doi.org\/10.1111\/liv.14370","archive":["Portico"],"relation":{},"ISSN":["1478-3223","1478-3231"],"issn-type":[{"value":"1478-3223","type":"print"},{"value":"1478-3231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,6]]},"assertion":[{"value":"2019-09-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-30","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-02-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}