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Recent studies have highlighted the effect of fructose on liver inflammation, fibrosis, and immune cell activation. However, little work summarizes the direct impact of fructose on macrophage infiltration, phenotype, and function within the liver. We demonstrate that chronic fructose diet decreased Kupffer cell populations while increasing transitioning monocytes. In addition, fructose increased fibrotic gene expression of collagen 1 alpha 1 (<jats:italic>Col1a1)<\/jats:italic> and tissue metallopeptidase inhibitor 1 (<jats:italic>Timp1)<\/jats:italic> as well as inflammatory gene expression of tumor necrosis factor alpha (<jats:italic>Tnfa)<\/jats:italic> and expression of transmembrane glycoprotein NMB (<jats:italic>Gpnmb)<\/jats:italic> in liver tissue compared to glucose and control diets. Single cell RNA sequencing (scRNAseq) revealed fructose elevated expression of matrix metallopeptidase 12 (<jats:italic>Mmp12)<\/jats:italic>, interleukin 1 receptor antagonist <jats:italic>(Il1rn),<\/jats:italic> and radical S-adenosyl methionine domain (<jats:italic>Rsad2)<\/jats:italic> in liver and hepatic macrophages. In vitro studies using IMKC and J774.1 cells demonstrated decreased viability when exposed to fructose. Additionally, fructose increased <jats:italic>Gpnmb<\/jats:italic>, <jats:italic>Tnfa<\/jats:italic>, <jats:italic>Mmp12<\/jats:italic>, <jats:italic>Il1rn<\/jats:italic>, and <jats:italic>Rsad2<\/jats:italic> in unpolarized IMKC. By mass spectrometry, C13 fructose tracing detected fructose metabolites in glycolysis and the pentose phosphate pathway (PPP). Inhibition of the PPP further increased fructose induced <jats:italic>Il6, Gpnmb<\/jats:italic>, <jats:italic>Mmp12<\/jats:italic>, <jats:italic>Il1rn<\/jats:italic>, and <jats:italic>Rsad2<\/jats:italic> in nonpolarized IMKC. Taken together, fructose decreases cell viability while upregulating resolution and anti-inflammatory associated genes in Kupffer cells.<\/jats:p>","DOI":"10.1038\/s41598-024-54272-w","type":"journal-article","created":{"date-parts":[[2024,2,18]],"date-time":"2024-02-18T15:02:36Z","timestamp":1708268556000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Fructose regulates the pentose phosphate pathway and induces an inflammatory and resolution phenotype in Kupffer cells"],"prefix":"10.1038","volume":"14","author":[{"given":"Mareca","family":"Lodge","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Scheidemantle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria R.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Cottam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Richard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denitra","family":"Breuer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kritika","family":"Shrestha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arion","family":"Kennedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,18]]},"reference":[{"key":"54272_CR1","doi-asserted-by":"publisher","first-page":"e2010224","DOI":"10.1001\/jamanetworkopen.2020.10224","volume":"3","author":"KJ Lancaster","year":"2020","unstructured":"Lancaster, K. 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