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Iron uptake is regulated at the intestine and is highly influenced by the gut microbiome. Blood from the intestines drains directly into the liver, informing iron status and gut microbiota status. Changes in either iron or the microbiome are tightly correlated with the development of metabolic dysfunction-associated steatotic liver disease (MASLD). To investigate the underlying mechanisms of the development of MASLD that connect altered iron metabolism and gut microbiota, we compared specific pathogen free (SPF) or germ-free (GF) mice, fed a normal or low-iron diet. SPF mice on a low-iron diet showed reduced serum triglycerides and MASLD. In contrast, GF low-iron diet-fed mice showed increased serum triglycerides and did not develop hepatic steatosis. SPF mice showed significant changes in liver lipid metabolism and increased insulin resistance that was dependent upon the presence of the gut microbiota. We report that total body loss of mitochondrial iron importer Mitoferrin2 (Mfrn2\u2212\/\u2212) exacerbated the development of MASLD on a low-iron diet with significant lipid metabolism alterations. Our study demonstrates a clear contribution of the gut microbiome, dietary iron, and Mfrn2 in the development of MASLD and metabolic syndrome.<\/jats:p>","DOI":"10.3390\/nu16121804","type":"journal-article","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T08:49:03Z","timestamp":1718009343000},"page":"1804","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Low-Iron Diet-Induced Fatty Liver Development Is Microbiota Dependent and Exacerbated by Loss of the Mitochondrial Iron Importer Mitoferrin2"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5237-8628","authenticated-orcid":false,"given":"Kendra A.","family":"Klag","sequence":"first","affiliation":[{"name":"Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0554-0730","authenticated-orcid":false,"given":"Rickesha","family":"Bell","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuan","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Seguin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Alan","family":"Maschek","sequence":"additional","affiliation":[{"name":"Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary","family":"Bronner","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA"},{"name":"Huntsman Cancer Institute, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5977-2350","authenticated-orcid":false,"given":"James E.","family":"Cox","sequence":"additional","affiliation":[{"name":"Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84132, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"June L.","family":"Round","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6520-0538","authenticated-orcid":false,"given":"Diane M.","family":"Ward","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41580-023-00648-1","article-title":"Mechanisms controlling cellular and systemic iron homeostasis","volume":"25","author":"Galy","year":"2024","journal-title":"Nat. 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