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We generated adult liver\u2010inducible ATG3 knockout mice (<jats:italic>Atg3<\/jats:italic><jats:sup><jats:italic>iLKO<\/jats:italic><\/jats:sup>) to characterize pathways linking hepatic autophagy with metabolic homeostasis. Genetic loss of hepatic autophagy leads to a reduction in 16\u2010h fasted glucose levels, a decrease in endogenous glucose production rates, and an increase in serum amino acids across the fed and fasted states. These changes collectively reflect a loss of hepatic gluconeogenic enzyme activity and not a general inability to degrade amino acids in the liver. Increased circulating glutamine levels resulting from this are associated with an induction of \u03b1\u2010cell hyperplasia, leading to constitutively elevated glucagon levels. However, the loss of hepatic gluconeogenesis renders these animals highly glucagon resistant. Collectively, our data demonstrate that loss of hepatic autophagy is sufficient to activate the hepatic \u03b1\u2010islet cell axis, leading to hyperglucagonemia with impaired glucose production.<\/jats:p>","DOI":"10.14814\/phy2.70381","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T02:55:24Z","timestamp":1748314524000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Loss of hepatic autophagy induces \u03b1\u2010cell proliferation through impaired glutamine\u2010dependent gluconeogenesis"],"prefix":"10.14814","volume":"13","author":[{"given":"Jesse N.","family":"Velasco\u2010Silva","sequence":"first","affiliation":[{"name":"Department of Biochemistry University of Utah  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph L.","family":"Wilkerson","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology University of Utah  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Ramos","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology University of Utah  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayden K.","family":"Low","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Utah  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0912-3424","authenticated-orcid":false,"given":"Faith","family":"Bowman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Utah  Salt Lake City Utah USA"},{"name":"Department of Nutrition and Integrative Physiology University of Utah  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberley 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