{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T20:50:08Z","timestamp":1790369408752,"version":"4.1.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2014,4,1]],"date-time":"2014-04-01T00:00:00Z","timestamp":1396310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) is activated in hepatic stellate cells (HSCs) by hypoxia and regulates genes important for tissue repair. Whether HIF-1\u03b1 is activated in HSCs after acute injury and contributes to liver regeneration, however, is not known. To investigate this, mice were generated with reduced levels of HIF-1\u03b1 in HSCs by crossing HIF-1\u03b1 floxed mice with mice that express Cre recombinase under control of the glial fibrillary acidic protein (GFAP) promoter (i.e., HIF-1\u03b1-GFAP Cre+ mice). These mice and control mice (i.e., HIF-1\u03b1-GFAP Cre\u2212 mice) were treated with a single dose of carbon tetrachloride, and liver injury and repair were assessed. After carbon tetrachloride, HIF-1\u03b1 was activated in HSCs. Although liver injury was not different between the two strains of mice, during resolution of injury, clearance of necrotic cells was decreased in HIF-1\u03b1-GFAP Cre+ mice. In these mice, the persistence of necrotic cells stimulated a fibrotic response characterized by extensive collagen deposition. Hepatic accumulation of macrophages, which clear necrotic cells from the liver after carbon tetrachloride, was not affected by HIF-1\u03b1 deletion in HSCs. Conversion of macrophages to M1-like, proinflammatory macrophages, which have increased phagocytic activity, however, was reduced in HIF-1\u03b1-GFAP Cre+ mice as indicated by a decrease in proinflammatory cytokines and a decrease in the percentage of Gr1hi macrophages. Collectively, these studies have identified a novel function for HSCs and HIF-1\u03b1 in orchestrating the clearance of necrotic cells from the liver and demonstrated a key role for HSCs in modulating macrophage phenotype during acute liver injury.<\/jats:p>","DOI":"10.4049\/jimmunol.1303195","type":"journal-article","created":{"date-parts":[[2014,3,18]],"date-time":"2014-03-18T05:36:36Z","timestamp":1395120996000},"page":"3847-3857","source":"Crossref","is-referenced-by-count":45,"title":["Hepatic Stellate Cells Orchestrate Clearance of Necrotic Cells in a Hypoxia-Inducible Factor-1\u03b1\u2013Dependent Manner by Modulating Macrophage Phenotype in Mice"],"prefix":"10.1093","volume":"192","author":[{"given":"Akie","family":"Mochizuki","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University , East Lansing, MI 48824"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Pace","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University , East Lansing, MI 48824"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl E","family":"Rockwell","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University , East Lansing, MI 48824"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine J","family":"Roth","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University , East Lansing, MI 48824"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Chow","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University , East Lansing, MI 48824"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate M","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University , East Lansing, MI 48824"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Albee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University , East Lansing, MI 48824"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University , East Lansing, MI 48824"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keara","family":"Towery","sequence":"additional","affiliation":[{"name":"Department of Pathobiology and Diagnostic Investigation, Michigan State University , East Lansing, MI 48824"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P","family":"Luyendyk","sequence":"additional","affiliation":[{"name":"Department of Pathobiology and Diagnostic Investigation, Michigan State University , East Lansing, MI 48824"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan L","family":"Copple","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University , East Lansing, MI 48824"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,4,15]]},"reference":[{"key":"2025032404223944900_r1","first-page":"5447","article-title":"A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation","volume":"12","author":"Semenza","year":"1992","journal-title":"Mol. 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