{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T06:06:22Z","timestamp":1785305182854,"version":"3.55.0"},"reference-count":117,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T00:00:00Z","timestamp":1644278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"National Council for Scientific and Technological Development","doi-asserted-by":"publisher","award":["CNPq 455,384\/2014-2"],"award-info":[{"award-number":["CNPq 455,384\/2014-2"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"name":"PAPES\/Fiocruz","award":["401,803\/2015-5."],"award-info":[{"award-number":["401,803\/2015-5."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Increased reactive oxidative stress, lipid peroxidation, inflammation, and fibrosis, which contribute to tissue damage and development and progression of nonalcoholic liver disease (NAFLD), play important roles in microcirculatory disorders. We investigated the effect of the modulatory properties of simvastatin (SV) on the liver and adipose tissue microcirculation as well as metabolic and oxidative stress parameters, including the advanced lipoxidation end product\u2013receptors of advanced glycation end products (ALE-RAGE) pathway. SV was administered to an NAFLD model constructed using a high-fat\u2013high-carbohydrate diet (HFHC). HFHC caused metabolic changes indicative of nonalcoholic steatohepatitis; treatment with SV protected the mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased leukocyte recruitment to hepatic and fat microcirculation, decreased hepatic stellate cell activation, and improved hepatic capillary network architecture and density. SV restored basal microvascular blood flow in the liver and adipose tissue and restored the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine. SV treatment restored antioxidant enzyme activity and decreased lipid peroxidation, ALE-RAGE pathway activation, steatosis, fibrosis, and inflammatory parameters. Thus, SV may improve microcirculatory function in NAFLD by downregulating oxidative and ALE-RAGE stress and improving steatosis, fibrosis, and inflammatory parameters.<\/jats:p>","DOI":"10.3390\/nu14030716","type":"journal-article","created":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T23:42:20Z","timestamp":1644363740000},"page":"716","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Simvastatin Improves Microcirculatory Function in Nonalcoholic Fatty Liver Disease and Downregulates Oxidative and ALE-RAGE Stress"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5511-7036","authenticated-orcid":false,"given":"Evelyn Nunes Goulart da Silva","family":"Pereira","sequence":"first","affiliation":[{"name":"Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Pavilh\u00e3o Oz\u00f3rio de Almeida Av. Brasil, 4365 (Room 14), Manguinhos, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz Peres de","family":"Araujo","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Pavilh\u00e3o Oz\u00f3rio de Almeida Av. Brasil, 4365 (Room 14), Manguinhos, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine Lino","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Pavilh\u00e3o Oz\u00f3rio de Almeida Av. Brasil, 4365 (Room 14), Manguinhos, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel Rangel","family":"Silvares","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Pavilh\u00e3o Oz\u00f3rio de Almeida Av. Brasil, 4365 (Room 14), Manguinhos, Rio de Janeiro 21040-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1920-8886","authenticated-orcid":false,"given":"Carolina Souza Machado","family":"Martins","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Pavilh\u00e3o Oz\u00f3rio de Almeida Av. 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