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The (pro)renin receptor (PRR) has recently been demonstrated to play a role in glucose and lipid metabolism. Here, we test the hypothesis that the PRR regulates the development of diet-induced hepatic steatosis and fibrosis. C57Bl\/6J mice were fed a high-fat diet (HFD) or normal-fat diet (NFD) with matching calories for 6 weeks. An 8-week methionine choline-deficient (MCD) diet was used to induce fibrosis. Two weeks following diet treatment, mice were implanted with a subcutaneous osmotic pump delivering either the peptide PRR antagonist, PRO20, or scrambled peptide for 4 or 6 weeks. Mice fed a 6-week HFD exhibited increased liver lipid accumulation and liver triglyceride content compared with NFD-fed mice. Importantly, PRO20 treatment reduced hepatic lipid accumulation in HFD-fed mice without affecting body weight or blood glucose. Furthermore, PRR antagonism attenuated HFD-induced steatosis, particularly microvesicular steatosis. In the MCD diet model, the percentage of collagen area was reduced in PRO20-treated compared with control mice. PRO20 treatment also significantly decreased levels of liver alanine aminotransferase, an indicator of liver damage, in MCD-fed mice compared with controls. Mechanistically, we found that PRR antagonism prevented HFD-induced increases in PPAR\u03b3 and glycerol-3-phosphate acyltransferase 3 expression in the liver. Taken together, our findings establish the involvement of the PRR in liver triglyceride synthesis and suggest the therapeutic potential of PRR antagonism for the treatment of liver steatosis and fibrosis in NAFLD.<\/jats:p>","DOI":"10.3390\/biom13010142","type":"journal-article","created":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T03:02:06Z","timestamp":1673319726000},"page":"142","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["(Pro)Renin Receptor Antagonism Attenuates High-Fat-Diet\u2013Induced Hepatic Steatosis"],"prefix":"10.3390","volume":"13","author":[{"given":"Ariana Julia B.","family":"Gayban","sequence":"first","affiliation":[{"name":"Departments of Pharmacology and Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, NV 89557, USA"},{"name":"Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, NV 89557, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1512-3030","authenticated-orcid":false,"given":"Lucas A. C.","family":"Souza","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, NV 89557, USA"},{"name":"Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, NV 89557, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvana G.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, NV 89557, USA"},{"name":"Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, NV 89557, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erick","family":"Regalado","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, NV 89557, USA"},{"name":"Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, NV 89557, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1350-0149","authenticated-orcid":false,"given":"Robert","family":"Kleemann","sequence":"additional","affiliation":[{"name":"Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333BE Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4138-0105","authenticated-orcid":false,"given":"Yumei","family":"Feng Earley","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, NV 89557, USA"},{"name":"Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, NV 89557, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1093\/qjmed\/hcp158","article-title":"Pathogenesis of non-alcoholic fatty liver disease","volume":"103","author":"Dowman","year":"2010","journal-title":"QJM Int. 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