{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:15:52Z","timestamp":1791389752245,"version":"4.3.3"},"reference-count":238,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T00:00:00Z","timestamp":1646006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB\/TRR296"],"award-info":[{"award-number":["SFB\/TRR296"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC1382"],"award-info":[{"award-number":["CRC1382"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Berlin Institute of Health at Charit\u00e9 - Universit\u00e4tsmedizin Berlin","award":["CSP 21-1"],"award-info":[{"award-number":["CSP 21-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nonalcoholic fatty liver disease (NAFLD) and its progressive form nonalcoholic steatohepatitis (NASH) comprise a spectrum of chronic liver diseases in the global population that can lead to end-stage liver disease and hepatocellular carcinoma (HCC). NAFLD is closely linked to the metabolic syndrome, and comorbidities such as type 2 diabetes, obesity and insulin resistance aggravate liver disease, while NAFLD promotes cardiovascular risk in affected patients. The pathomechanisms of NAFLD are multifaceted, combining hepatic factors including lipotoxicity, mechanisms of cell death and liver inflammation with extrahepatic factors including metabolic disturbance and dysbiosis. Nuclear receptors (NRs) are a family of ligand-controlled transcription factors that regulate glucose, fat and cholesterol homeostasis and modulate innate immune cell functions, including liver macrophages. In parallel with metabolic derangement in NAFLD, altered NR signaling is frequently observed and might be involved in the pathogenesis. Therapeutically, clinical data indicate that single drug targets thus far have been insufficient for reaching patient-relevant endpoints. Therefore, combinatorial treatment strategies with multiple drug targets or drugs with multiple mechanisms of actions could possibly bring advantages, by providing a more holistic therapeutic approach. In this context, peroxisome proliferator-activated receptors (PPARs) and other NRs are of great interest as they are involved in wide-ranging and multi-organ activities associated with NASH progression or regression. In this review, we summarize recent advances in understanding the pathogenesis of NAFLD, focusing on mechanisms of cell death, immunometabolism and the role of NRs. We outline novel therapeutic strategies and discuss remaining challenges.<\/jats:p>","DOI":"10.3390\/ijms23052668","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T20:11:14Z","timestamp":1646079074000},"page":"2668","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":98,"title":["Nuclear Receptors Linking Metabolism, Inflammation, and Fibrosis in Nonalcoholic Fatty Liver Disease"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2662-6127","authenticated-orcid":false,"given":"Tobias","family":"Puengel","sequence":"first","affiliation":[{"name":"Department of Hepatology & Gastroenterology, Charit\u00e9 Universit\u00e4tsmedizin Berlin, Campus Virchow-Klinikum and Campus Charit\u00e9 Mitte, 13353 Berlin, Germany"},{"name":"Berlin Institute of Health (BIH), 10178 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1035-4895","authenticated-orcid":false,"given":"Hanyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hepatology & Gastroenterology, Charit\u00e9 Universit\u00e4tsmedizin Berlin, Campus Virchow-Klinikum and Campus Charit\u00e9 Mitte, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6002-9986","authenticated-orcid":false,"given":"Adrien","family":"Guillot","sequence":"additional","affiliation":[{"name":"Department of Hepatology & Gastroenterology, Charit\u00e9 Universit\u00e4tsmedizin Berlin, Campus Virchow-Klinikum and Campus Charit\u00e9 Mitte, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Heymann","sequence":"additional","affiliation":[{"name":"Department of Hepatology & Gastroenterology, Charit\u00e9 Universit\u00e4tsmedizin Berlin, Campus Virchow-Klinikum and Campus Charit\u00e9 Mitte, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6206-0226","authenticated-orcid":false,"given":"Frank","family":"Tacke","sequence":"additional","affiliation":[{"name":"Department of Hepatology & Gastroenterology, Charit\u00e9 Universit\u00e4tsmedizin Berlin, Campus Virchow-Klinikum and Campus Charit\u00e9 Mitte, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6195-3866","authenticated-orcid":false,"given":"Moritz","family":"Peiseler","sequence":"additional","affiliation":[{"name":"Department of Hepatology & Gastroenterology, Charit\u00e9 Universit\u00e4tsmedizin Berlin, Campus Virchow-Klinikum and Campus Charit\u00e9 Mitte, 13353 Berlin, Germany"},{"name":"Berlin Institute of Health (BIH), 10178 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1053\/j.gastro.2010.09.038","article-title":"Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: A prospective study","volume":"140","author":"Williams","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrgastro.2017.109","article-title":"Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention","volume":"15","author":"Younossi","year":"2018","journal-title":"Nat. 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