{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:59:30Z","timestamp":1785405570257,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,3]]},"reference-count":36,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"https:\/\/ror.org\/05qdwtz81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R35CA220483"],"award-info":[{"award-number":["R35CA220483"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["5T32CA009140"],"award-info":[{"award-number":["5T32CA009140"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"crossref","award":["PF-23-1034739-01-TBE"],"award-info":[{"award-number":["PF-23-1034739-01-TBE"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001021","name":"Damon Runyon Cancer Research Foundation","doi-asserted-by":"crossref","award":["DRG2497"],"award-info":[{"award-number":["DRG2497"]}],"id":[{"id":"10.13039\/100001021","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The hepatic urea cycle is consistently suppressed in liver disease and hepatocellular carcinoma (HCC), but whether loss of individual enzymes contributes to disease initiation and progression remains unknown. Using mice with hepatocyte-specific deletion of argininosuccinate synthase 1 (ASS1), the urea cycle enzyme that condenses citrulline and aspartate into argininosuccinate, we investigated the role of ASS1 in diet and carcinogen-induced liver disease progression. We found that complete loss of hepatic\n                  <jats:italic>Ass1<\/jats:italic>\n                  is lethal, but high fat diet extends lifespan. Unexpectedly, animals with approximately 85% loss of hepatic\n                  <jats:italic>Ass1<\/jats:italic>\n                  are completed protected from diet-induced obesity, liver steatosis, fibrosis, and HCC. We determined that hepatic\n                  <jats:italic>Ass1<\/jats:italic>\n                  loss activates fatty acid oxidation in peripheral oxidative tissues leading to increased energy expenditure and protection from disease phenotypes. Moreover, targeting\n                  <jats:italic>Ass1<\/jats:italic>\n                  after obesity onset promotes weight loss and reverses liver steatosis. These findings implicate hepatic ASS1 as a novel regulator of whole-body lipid metabolism that can be targeted to prevent obesity, liver disease, and HCC.\n                <\/jats:p>","DOI":"10.64898\/2026.06.02.729618","type":"posted-content","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T13:30:15Z","timestamp":1780493415000},"source":"Crossref","is-referenced-by-count":0,"title":["Argininosuccinate Synthase 1 links hepatic urea cycle to whole body lipid metabolism"],"prefix":"10.64898","author":[{"given":"Laura C.","family":"Kim","sequence":"first","affiliation":[{"name":"Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas P.","family":"Lesner","sequence":"additional","affiliation":[{"name":"Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanyan","family":"Cai","sequence":"additional","affiliation":[{"name":"Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Han","sequence":"additional","affiliation":[{"name":"Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Woo","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Institute, Institute of Diabetes Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy P.","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan J.","family":"Coffey","sequence":"additional","affiliation":[{"name":"Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Zheng","sequence":"additional","affiliation":[{"name":"Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan L.","family":"Brown","sequence":"additional","affiliation":[{"name":"Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clementina","family":"Mesaros","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoltan","family":"Arany","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Institute, Institute of Diabetes Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Celeste","family":"Simon","sequence":"additional","affiliation":[{"name":"Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026070714000999000_2026.06.02.729618v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0054-z"},{"key":"2026070714000999000_2026.06.02.729618v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2022.06.010"},{"key":"2026070714000999000_2026.06.02.729618v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.04.009"},{"key":"2026070714000999000_2026.06.02.729618v2.4","doi-asserted-by":"crossref","unstructured":"Khare, S. et al. ASS1 and ASL suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism. 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