{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:32:54Z","timestamp":1785407574949,"version":"3.56.0"},"reference-count":16,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University of Warsaw"},{"id":[{"id":"https:\/\/ror.org\/04p2y4s44","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: A high-fat diet (HFD) contributes to cardiometabolic disease. Gut microbiota-derived metabolites may participate in this process, but their contribution to lipid regulation is not well defined. Indoxyl sulfate (IS), a microbiota-derived metabolite, has been linked to vascular and metabolic dysfunction. Its role in lipid metabolism remains unclear. Methods: In Part A, plasma and urinary concentrations of IS were measured in plasma and urine from HFD-fed rats in which dyslipidemia had developed, together with controls. In Part B, HepG2 cells were exposed to IS, and cell viability and selected cholesterol metabolism-related transcripts and proteins were assessed. In Part C, 10-week-old, male Sprague\u2013Dawley rats maintained on a standard diet received vehicle or IS at two doses for 8 weeks. Hepatic expression of LDLR, SREBP-2, HMG-CoA reductase, and related cholesterol metabolism markers were measured by quantitative real-time PCR and Western blotting. Results: In Part A, higher plasma IS concentrations and higher daily urinary IS excretion were found in samples collected from HFD-fed rats compared to controls. In HepG2 cells, IS reduced cell viability at higher concentrations and increased LDLR mRNA and protein expression. In IS-treated rats, total cholesterol, LDL-cholesterol, and triglycerides increased in a dose-dependent manner. Hepatic SREBP-2 and HMG-CoA reductase protein levels were increased at both IS doses, whereas LDLR protein abundance was increased at the higher dose. Moreover, serum PCSK9 levels were reduced in IS-treated rats. Conclusion: IS increased in HFD-fed rats. IS altered cholesterol metabolism-related pathways in HepG2 cells and in rats. In vivo IS administration increased circulating lipids and hepatic proteins involved in cholesterol synthesis and uptake. These findings indicate that IS may contribute to disturbed lipid homeostasis, although its role in HFD-induced dyslipidemia requires further mechanistic confirmation.<\/jats:p>","DOI":"10.3390\/nu18132160","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T09:34:11Z","timestamp":1783071251000},"page":"2160","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Indoxyl Sulfate, a Gut Microbiota-Derived Metabolite, Modulates Hepatic Cholesterol Metabolism via SREBP-2\/HMG-CoA Reductase Upregulation in Rats"],"prefix":"10.3390","volume":"18","author":[{"given":"Mateusz","family":"Szudzik","sequence":"first","affiliation":[{"name":"Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Pawi\u0144skiego 3c Street, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0299-9641","authenticated-orcid":false,"given":"Miko\u0142aj","family":"Zajdel","sequence":"additional","affiliation":[{"name":"Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Pawi\u0144skiego 3c Street, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Laskowska","sequence":"additional","affiliation":[{"name":"Centre for Preclinical Research and Technology (CePT), Department of Pharmaceutical Microbiology and Bioanalysis, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Hutsch","sequence":"additional","affiliation":[{"name":"Department of Pathology and Veterinary Diagnostics, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-776 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0088-8284","authenticated-orcid":false,"given":"Marcin","family":"Ufnal","sequence":"additional","affiliation":[{"name":"Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Pawi\u0144skiego 3c Street, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"22796","DOI":"10.1038\/s41598-024-74193-y","article-title":"Normal caloric intake with high-fat diet induces metabolic dysfunction-associated steatotic liver disease and dyslipidemia without obesity in rats","volume":"14","author":"Szudzik","year":"2024","journal-title":"Sci. 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