{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T07:21:43Z","timestamp":1781248903562,"version":"3.54.1"},"reference-count":78,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>We wished to understand the metabolic reprogramming underlying liver fibrosis progression in mice. Administration to male C57BL\/6J mice of the hepatotoxins carbon tetrachloride (CCl4), thioacetamide (TAA), or a 60% high-fat diet, choline-deficient, amino-acid-defined diet (HF-CDAA) was conducted using standard protocols. Livers collected at different times were analyzed by gas chromatography\u2013mass spectrometry-based metabolomics. RNA was extracted from liver and assayed by qRT-PCR for mRNA expression of 11 genes potentially involved in the synthesis of ascorbic acid from hexoses, Gck, Adpgk, Hk1, Hk2, Ugp2, Ugdh, Ugt1a1, Akr1a4, Akr1b3, Rgn and Gulo. All hepatotoxins resulted in similar metabolic changes during active fibrogenesis, despite different etiology and resultant scarring pattern. Diminished hepatic glucose, galactose, fructose, pentose phosphate pathway intermediates, glucuronic acid and long-chain fatty acids were compensated by elevated ascorbate and the product of collagen prolyl 4-hydroxylase, succinate and its downstream metabolites fumarate and malate. Recovery from the HF-CDAA diet challenge (F2 stage fibrosis) after switching to normal chow was accompanied by increased glucose, galactose, fructose, ribulose 5-phosphate, glucuronic acid, the ascorbate metabolite threonate and diminished ascorbate. During the administration of CCl4, TAA and HF-CDAA, aldose reductase Akr1b3 transcription was induced six- to eightfold, indicating increased conversion of glucuronic acid to gulonic acid, a precursor of ascorbate synthesis. Triggering hepatic fibrosis by three independent mechanisms led to the hijacking of glucose and galactose metabolism towards ascorbate synthesis, to satisfy the increased demand for ascorbate as a cofactor for prolyl 4-hydroxylase for mature collagen production. This metabolic reprogramming and causal gene expression changes were reversible. The increased flux in this pathway was mediated predominantly by increased transcription of aldose reductase Akr1b3.<\/jats:p>","DOI":"10.3390\/cells12030485","type":"journal-article","created":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T06:11:53Z","timestamp":1675318313000},"page":"485","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Metabolic Hijacking of Hexose Metabolism to Ascorbate Synthesis Is the Unifying Biochemical Basis of Murine Liver Fibrosis"],"prefix":"10.3390","volume":"12","author":[{"given":"Diren","family":"Beyo\u011flu","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA"},{"name":"Arthur G. Zupko Institute for Systems Pharmacology and Pharmacogenomics, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinzhu","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Disha","family":"Skelton-Badlani","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Zong","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7973-942X","authenticated-orcid":false,"given":"Yury V.","family":"Popov","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6143-1520","authenticated-orcid":false,"given":"Jeffrey R.","family":"Idle","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA"},{"name":"Arthur G. Zupko Institute for Systems Pharmacology and Pharmacogenomics, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201, USA"},{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis","volume":"115","author":"Bataller","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"787748","DOI":"10.3389\/fphar.2022.787748","article-title":"Molecular Mechanisms and Potential New Therapeutic Drugs for Liver Fibrosis","volume":"13","author":"Wang","year":"2022","journal-title":"Front. 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