{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T22:03:04Z","timestamp":1769551384704,"version":"3.49.0"},"reference-count":79,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T00:00:00Z","timestamp":1692057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"D.R.B. Principal Investigator","doi-asserted-by":"publisher","award":["R01 AA027502"],"award-info":[{"award-number":["R01 AA027502"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, hepatocyte ballooning, and inflammation and may progress to include increasingly severe fibrosis, which portends more serious disease and is predictive of patient mortality. Diagnostic and therapeutic options for NASH fibrosis are limited, and the underlying fibrogenic pathways are under-explored. Cell communication network factor 2 (CCN2) is a well-characterized pro-fibrotic molecule, but its production in and contribution to NASH fibrosis requires further study. Hepatic CCN2 expression was significantly induced in NASH patients with F3\u2013F4 fibrosis and was positively correlated with hepatic Col1A1, Col1A2, Col3A1, or \u03b1SMA expression. When wild-type (WT) or transgenic (TG) Swiss mice expressing enhanced green fluorescent protein (EGFP) under the control of the CCN2 promoter were fed up to 7 weeks with control or choline-deficient, amino-acid-defined diet with high (60%) fat (CDAA-HF), the resulting NASH-like hepatic pathology included a profound increase in CCN2 or EGFP immunoreactivity in activated hepatic stellate cells (HSC) and in fibroblasts and smooth muscle cells of the vasculature, with little or no induction of CCN2 in other liver cell types. In the context of CDAA-HF diet-induced NASH, Balb\/c TG mice expressing human CCN2 under the control of the albumin promoter exhibited exacerbated deposition of interstitial hepatic collagen and activated HSC compared to WT mice. In vitro, palmitic acid-treated hepatocytes produced extracellular vesicles (EVs) that induced CCN2, Col1A1, and \u03b1SMA in HSC. Hepatic CCN2 may aid the assessment of NASH fibrosis severity and, together with pro-fibrogenic EVs, is a therapeutic target for reducing NASH fibrosis.<\/jats:p>","DOI":"10.3390\/ijms241612823","type":"journal-article","created":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T11:06:16Z","timestamp":1692097576000},"page":"12823","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Production, Exacerbating Effect, and EV-Mediated Transcription of Hepatic CCN2 in NASH: Implications for Diagnosis and Therapy of NASH Fibrosis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6919-6262","authenticated-orcid":false,"given":"Xinlei","family":"Li","sequence":"first","affiliation":[{"name":"Center for Clinical and Translational Research, The Research Institute, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruju","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Clinical and Translational Research, The Research Institute, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sherri","family":"Kemper","sequence":"additional","affiliation":[{"name":"Center for Clinical and Translational Research, The Research Institute, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8651-6486","authenticated-orcid":false,"given":"David R.","family":"Brigstock","sequence":"additional","affiliation":[{"name":"Center for Clinical and Translational Research, The Research Institute, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"},{"name":"Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH 43212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1056\/NEJMra1503519","article-title":"Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis","volume":"377","author":"Diehl","year":"2017","journal-title":"N. 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