{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T23:48:14Z","timestamp":1788997694520,"version":"build-2803163510"},"reference-count":70,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,17]],"date-time":"2022-09-17T00:00:00Z","timestamp":1663372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UC-MEXUS Consejo Nacional de Ciencia y Tecnologia (CONACyT)","award":["NCMHD9T37MD001480"],"award-info":[{"award-number":["NCMHD9T37MD001480"]}]},{"DOI":"10.13039\/100000002","name":"University of California","doi-asserted-by":"publisher","award":["NCMHD9T37MD001480"],"award-info":[{"award-number":["NCMHD9T37MD001480"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) affects up to 20% of the world\u2019s population. Overactivation of the angiotensin receptor type 1 (AT1) contributes to metabolic dysfunction and increased oxidant production, which are associated with NAFLD and impaired hepatic lipid metabolism. Nuclear factor erythroid-2-related factor 2 (Nrf2) regulates the expression of antioxidant phase II genes by binding to the antioxidant response element (ARE); however, the mechanisms by which AT1 contributes to this pathway during the progression of NAFLD remain unresolved. To investigate hepatic Nrf2 response to a hyperglycemic challenge, we studied three groups of rats (male, 10-weeks-old): (1) untreated, lean Long Evans Tokushima Otsuka (LETO), (2) untreated, obese Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + angiotensin receptor blocker (OLETF + ARB; 10 mg olmesartan\/kg\/d \u00d7 6 weeks). Livers were collected after overnight fasting (T0; baseline), and 1 h and 2 h post-oral glucose load. At baseline, chronic AT1 blockade increased nuclear Nrf2 content, reduced expression of glutamate-cysteine ligase catalytic (GCLC) subunit, glutathione peroxidase 1 (GPx1), and superoxide dismutase 2 (SOD2), mitochondrial catalase activity, and hepatic 4-hydroxy-2-nonenal (4-HNE) content. The expression of hepatic interleukin-1 beta (IL-1\u03b2) and collagen type IV, which are associated with liver fibrosis, were decreased with AT1 blockade. Glucose increased Nrf2 translocation in OLETF but was reduced in ARB, suggesting that glucose induces the need for antioxidant defense that is ameliorated with ARB. These results suggest that overactivation of AT1 promotes oxidant damage by suppressing Nrf2 and contributing to hepatic fibrosis associated with NAFLD development.<\/jats:p>","DOI":"10.3390\/ijms231810897","type":"journal-article","created":{"date-parts":[[2022,9,18]],"date-time":"2022-09-18T23:39:22Z","timestamp":1663544362000},"page":"10897","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Glucose Increases Hepatic Mitochondrial Antioxidant Enzyme Activities in Insulin Resistant Rats Following Chronic Angiotensin Receptor Blockade"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4671-3201","authenticated-orcid":false,"given":"Jose A.","family":"Godoy-Lugo","sequence":"first","affiliation":[{"name":"Department of Molecular & Cell Biology, School of Natural Sciences, University of California, Merced, CA 95343, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0095-5344","authenticated-orcid":false,"given":"Max A.","family":"Thorwald","sequence":"additional","affiliation":[{"name":"Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dora A.","family":"Mendez","sequence":"additional","affiliation":[{"name":"Department of Molecular & Cell Biology, School of Natural Sciences, University of California, Merced, CA 95343, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Molecular & Cell Biology, School of Natural Sciences, University of California, Merced, CA 95343, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Nakano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kagawa Medical University, Kagawa 761-0793, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5971-820X","authenticated-orcid":false,"given":"Akira","family":"Nishiyama","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kagawa Medical University, Kagawa 761-0793, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3715-7194","authenticated-orcid":false,"given":"Rudy M.","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Department of Molecular & Cell Biology, School of Natural Sciences, University of California, Merced, CA 95343, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s41575-019-0144-8","article-title":"Past, Present and Future Perspectives in Nonalcoholic Fatty Liver Disease","volume":"16","author":"Sanyal","year":"2019","journal-title":"Nat. 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