{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T05:37:47Z","timestamp":1779341867479,"version":"3.51.4"},"reference-count":124,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T00:00:00Z","timestamp":1663804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Telethon Foundation","doi-asserted-by":"publisher","award":["GGP15219"],"award-info":[{"award-number":["GGP15219"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Telethon Foundation","doi-asserted-by":"publisher","award":["\u201cCerebro-NGS.TO\u201d"],"award-info":[{"award-number":["\u201cCerebro-NGS.TO\u201d"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Telethon Foundation","doi-asserted-by":"publisher","award":["2018-21"],"award-info":[{"award-number":["2018-21"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondazione CRT (Cassa di Risparmio di Torino)","award":["GGP15219"],"award-info":[{"award-number":["GGP15219"]}]},{"name":"Fondazione CRT (Cassa di Risparmio di Torino)","award":["\u201cCerebro-NGS.TO\u201d"],"award-info":[{"award-number":["\u201cCerebro-NGS.TO\u201d"]}]},{"name":"Fondazione CRT (Cassa di Risparmio di Torino)","award":["2018-21"],"award-info":[{"award-number":["2018-21"]}]},{"name":"University of Torino","award":["GGP15219"],"award-info":[{"award-number":["GGP15219"]}]},{"name":"University of Torino","award":["\u201cCerebro-NGS.TO\u201d"],"award-info":[{"award-number":["\u201cCerebro-NGS.TO\u201d"]}]},{"name":"University of Torino","award":["2018-21"],"award-info":[{"award-number":["2018-21"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>KRIT1 loss-of-function mutations underlie the pathogenesis of Cerebral Cavernous Malformation (CCM), a major vascular disease affecting the central nervous system (CNS). However, KRIT1 is also expressed outside the CNS and modulates key regulators of metabolic and oxy-inflammatory pathways, including the master transcription factor FoxO1, suggesting a widespread functional significance. Herein, we show that the KRIT1\/FoxO1 axis is implicated in liver metabolic functions and antioxidative\/antiglycative defenses. Indeed, by performing comparative studies in KRIT1 heterozygous (KRIT1+\/\u2212) and wild-type mice, we found that KRIT1 haploinsufficiency resulted in FoxO1 expression\/activity downregulation in the liver, and affected hepatic FoxO1-dependent signaling pathways, which are markers of major metabolic processes, including gluconeogenesis, glycolysis, mitochondrial respiration, and glycogen synthesis. Moreover, it caused sustained activation of the master antioxidant transcription factor Nrf2, hepatic accumulation of advanced glycation end-products (AGEs), and abnormal expression\/activity of AGE receptors and detoxifying systems. Furthermore, it was associated with an impairment of food intake, systemic glucose disposal, and plasma levels of insulin. Specific molecular alterations detected in the liver of KRIT1+\/\u2212 mice were also confirmed in KRIT1 knockout cells. Overall, our findings demonstrated, for the first time, that KRIT1 haploinsufficiency affects glucose homeostasis and liver metabolic and antioxidative\/antiglycative functions, thus inspiring future basic and translational studies.<\/jats:p>","DOI":"10.3390\/ijms231911151","type":"journal-article","created":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T21:10:05Z","timestamp":1663881005000},"page":"11151","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Heterozygous Loss of KRIT1 in Mice Affects Metabolic Functions of the Liver, Promoting Hepatic Oxidative and Glycative Stress"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0104-6129","authenticated-orcid":false,"given":"Raffaella","family":"Mastrocola","sequence":"first","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"},{"name":"CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6336-1442","authenticated-orcid":false,"given":"Eleonora","family":"Aimaretti","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2529-2006","authenticated-orcid":false,"given":"Gustavo","family":"Ferreira Alves","sequence":"additional","affiliation":[{"name":"Department of Neurosciences \u201cRita Levi Montalcini\u201d, University of Torino, 10126 Torino (TO), Italy"},{"name":"Department of Pharmacology, Federal University of Santa Catarina, Florian\u00f3polis 88040-900, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia Sofia","family":"Cento","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Fornelli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"},{"name":"CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0726-3025","authenticated-orcid":false,"given":"Federica","family":"Dal Bello","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino (TO), Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Ferraris","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"},{"name":"CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Goitre","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"},{"name":"CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8512-6080","authenticated-orcid":false,"given":"Andrea","family":"Perrelli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"},{"name":"CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"},{"name":"Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9761-2959","authenticated-orcid":false,"given":"Saverio Francesco","family":"Retta","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"},{"name":"CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano (TO), Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/nrneurol.2009.177","article-title":"Cavernous malformations: Natural history, diagnosis and treatment","volume":"5","author":"Batra","year":"2009","journal-title":"Nat. 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