{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:50:04Z","timestamp":1791996604884,"version":"4.4.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2019,2,27]],"date-time":"2019-02-27T00:00:00Z","timestamp":1551225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2019,2,27]],"date-time":"2019-02-27T00:00:00Z","timestamp":1551225600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:p>A crucial component of nonalcoholic fatty liver disease (NAFLD) pathogenesis is lipid stress, which may contribute to hepatic inflammation and activation of innate immunity in the liver. However, little is known regarding how dietary lipids, including fat and cholesterol, may facilitate innate immune activation <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. We hypothesized that dietary fat and cholesterol drive NAFLD progression to steatohepatitis and hepatic fibrosis by altering the transcription and phenotype of hepatic macrophages. This hypothesis was tested by using RNA\u2010sequencing methods to characterize and analyze sort\u2010purified hepatic macrophage populations that were isolated from mice fed diets with varying amounts of fat and cholesterol. The addition of cholesterol to a high\u2010fat diet triggered hepatic pathology reminiscent of advanced nonalcoholic steatohepatitis (NASH) in humans characterized by signs of cholesterol dysregulation, generation of oxidized low\u2010density lipoprotein, increased recruitment of hepatic macrophages, and significant fibrosis. RNA\u2010sequencing analyses of hepatic macrophages in this model revealed that dietary cholesterol induced a tissue repair and regeneration phenotype in Kupffer cells (KCs) and recruited infiltrating macrophages to a greater degree than fat. Furthermore, comparison of diseased KCs and infiltrating macrophages revealed that these two macrophage subsets are transcriptionally diverse. Finally, direct stimulation of murine and human macrophages with oxidized low\u2010density lipoprotein recapitulated some of the transcriptional changes observed in the RNA\u2010sequencing study. These findings indicate that fat and cholesterol synergize to alter macrophage phenotype, and they also challenge the dogma that KCs are purely proinflammatory in NASH. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: This comprehensive view of macrophage populations in NASH indicates mechanisms by which cholesterol contributes to NASH progression and identifies potential therapeutic targets for this common disease.<\/jats:p>","DOI":"10.1002\/hep.30401","type":"journal-article","created":{"date-parts":[[2018,12,5]],"date-time":"2018-12-05T16:41:25Z","timestamp":1544028085000},"page":"67-83","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":105,"title":["Dietary Lipids Differentially Shape Nonalcoholic Steatohepatitis Progression and the Transcriptome of Kupffer Cells and Infiltrating Macrophages"],"prefix":"10.1097","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3120-0123","authenticated-orcid":false,"given":"Brett","family":"McGettigan","sequence":"first","affiliation":[{"name":"Division of Gastroenterology & Hepatology, Department of Medicine,University of Colorado Denver,Denver,CO"},{"name":"Department of Immunology,University of Colorado Denver,Denver,CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2162-2821","authenticated-orcid":false,"given":"Rachel","family":"McMahan","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology & Hepatology, Department of Medicine,University of Colorado Denver,Denver,CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Orlicky","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Colorado Denver,Denver,CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Burchill","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology & Hepatology, Department of Medicine,University of Colorado Denver,Denver,CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Danhorn","sequence":"additional","affiliation":[{"name":"Division of Biostatistics and Bioinformatics,National Jewish Health,Denver,CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashanth","family":"Francis","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology & Hepatology, Department of Medicine,University of Colorado Denver,Denver,CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin Ling","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology & Hepatology, Department of Medicine,University of Colorado Denver,Denver,CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Golden\u2010Mason","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology & Hepatology, Department of Medicine,University of Colorado Denver,Denver,CO"},{"name":"Department of Immunology,University of Colorado Denver,Denver,CO"},{"name":"Department of Medicine,University of Southern California,Los Angeles,CA"},{"name":"USC Research Center for Liver Diseases,Los Angeles,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia V.","family":"Jakubzick","sequence":"additional","affiliation":[{"name":"Department of Immunology,University of Colorado Denver,Denver,CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo R.","family":"Rosen","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology & Hepatology, Department of Medicine,University of Colorado Denver,Denver,CO"},{"name":"Department of Immunology,University of Colorado Denver,Denver,CO"},{"name":"Department of Medicine,University of Southern California,Los Angeles,CA"},{"name":"USC Research Center for Liver Diseases,Los Angeles,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,2,27]]},"reference":[{"key":"hep30401-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nrgastro.2013.149","article-title":"From NAFLD to NASH to cirrhosis\u2014new insights into disease mechanisms","volume":"10","year":"2013","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep30401-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1097\/MOL.0b013e32834c7cfc","article-title":"Nonalcoholic steatohepatitis: the therapeutic challenge of a global epidemic","volume":"22","year":"2011","journal-title":"Curr Opin 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