{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T03:53:53Z","timestamp":1788580433381,"version":"build-2803163510"},"reference-count":52,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T00:00:00Z","timestamp":1626912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chang Gung Memorial Hospital, Linkuo, Taiwan","award":["CMRPD1B0261, CMRPD1B0262, CMRPD1D0351, CMRPD1D0352"],"award-info":[{"award-number":["CMRPD1B0261, CMRPD1B0262, CMRPD1D0351, CMRPD1D0352"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hypoxia and hepatosteatosis microenvironments are fundamental traits of nonalcoholic fatty liver disease (NAFLD). Hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with NAFLD, whereas the route and regulation of lipid droplets (LDs) and macrophage polarization related to systemic inflammation in NAFLD is unknown. Losartan is an angiotensin II receptor antagonist, that approved portal hypertension and related HIF-1\u03b1 pathways in hepatic injury models. Here, we show that losartan in a murine model of NAFLD significantly decreased hepatic de novo lipogenesis (DNL) as well as suppressed lipid droplets (LDs), LD-associated proteins, perilipins (PLINs), and cell-death-inducing DNA-fragmentation-factor (DFF45)-like effector (CIDE) family in liver and epididymal white adipose tissues (EWAT) of ob\/ob mice. Obesity-mediated macrophage M1 activation was also required for HIF-1\u03b1 expression in the liver and EWAT of ob\/ob mice. Administration of losartan significantly diminishes obesity-enhanced macrophage M1 activation and suppresses hepatosteatosis. Moreover, HIF-1\u03b1-mediated mitochondrial dysfunction was reversed in ob\/ob mice treated with losartan. Together, the regulation of HIF-1\u03b1 controls LDs protein expression and macrophage polarization, which highlights a potential target for losartan in NAFLD.<\/jats:p>","DOI":"10.3390\/ijms22157841","type":"journal-article","created":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T22:35:31Z","timestamp":1626993331000},"page":"7841","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Losartan Prevents Hepatic Steatosis and Macrophage Polarization by Inhibiting HIF-1\u03b1 in a Murine Model of NAFLD"],"prefix":"10.3390","volume":"22","author":[{"given":"Cheng-Hui","family":"Wang","sequence":"first","affiliation":[{"name":"Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsuan-Miao","family":"Liu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Traditional Chinese Medicine, School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Yu","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung City 204, Taiwan"},{"name":"Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5231-9932","authenticated-orcid":false,"given":"Tse-Hung","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung City 204, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4097-2085","authenticated-orcid":false,"given":"Tzung-Yan","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"},{"name":"Graduate Institute of Traditional Chinese Medicine, School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"},{"name":"Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung City 204, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1074\/mcp.RA118.000961","article-title":"Hepatic mitochondrial defects in a nonalcoholic fatty liver disease mouse model are associated with increased degradation of oxidative phosphorylation subunits","volume":"17","author":"Lee","year":"2018","journal-title":"Mol. 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