{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:30:46Z","timestamp":1791304246406,"version":"4.3.1"},"reference-count":52,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T00:00:00Z","timestamp":1713312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Doktor Robert Pfleger funding (Germany)"},{"name":"intramural funding (FORUN program, University Medical Center Rostock)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Anorexia nervosa (AN) induces organ dysfunction caused by malnutrition, including liver damage leading to a rise in transaminases due to hepatocyte damage. The underlying pathophysiology of starvation-induced liver damage is poorly understood. We investigate the effect of a 25% body weight reduction on murine livers in a mouse model and examine possible underlying mechanisms of starvation-induced liver damage. Female mice received a restricted amount of food with access to running wheels until a 25% weight reduction was achieved. This weight reduction was maintained for two weeks to mimic chronic starvation. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured spectrophotometrically. Liver fat content was analyzed using an Oil Red O stain, and liver glycogen was determined using a Periodic acid\u2013Schiff (PAS) stain. Immunohistochemical stains were used to investigate macrophages, proliferation, apoptosis, and autophagy. Starvation led to an elevation of AST and ALT values, a decreased amount of liver fat, and reduced glycogen deposits. The density of F4\/80+ macrophage numbers as well as proliferating KI67+ cells were decreased by starvation, while apoptosis was not altered. This was paralleled by an increase in autophagy-related protein staining. Increased transaminase values suggest the presence of liver damage in the examined livers of starved mice. The observed starvation-induced liver damage may be attributed to increased autophagy. Whether other mechanisms play an additional role in starvation-induced liver damage remains to be investigated.<\/jats:p>","DOI":"10.3390\/nu16081191","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T07:54:36Z","timestamp":1713340476000},"page":"1191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Starvation in Mice Induces Liver Damage Associated with Autophagy"],"prefix":"10.3390","volume":"16","author":[{"given":"Katharina","family":"Schuster","sequence":"first","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Staffeld","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelie","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"B\u00f6ge","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Lang","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Kuhla","sequence":"additional","affiliation":[{"name":"Rudolf-Zenker-Institute for Experimental Surgery, Medical University Rostock, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Frintrop","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.chc.2014.08.003","article-title":"Adolescent eating disorders: Update on definitions, symptomatology, epidemiology, and comorbidity","volume":"24","year":"2015","journal-title":"Child. Adolesc. Psychiatr. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1053\/j.gastro.2008.05.055","article-title":"Acute liver cell damage in patients with anorexia nervosa: A possible role of starvation-induced hepatocyte autophagy","volume":"135","author":"Rautou","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1002\/eat.20889","article-title":"Severe anorexia nervosa: Outcomes from a medical stabilization unit","volume":"45","author":"Gaudiani","year":"2012","journal-title":"Int. J. Eat. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/eat.22436","article-title":"Liver dysfunction in patients with severe anorexia nervosa","volume":"49","author":"Rosen","year":"2016","journal-title":"Int. J. Eat. Disord."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.clnu.2012.08.020","article-title":"Hypertransaminasemia in severely malnourished adult anorexia nervosa patients: Risk factors and evolution under enteral nutrition","volume":"32","author":"Hanachi","year":"2013","journal-title":"Clin. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1001\/archinte.165.5.561","article-title":"Medical findings in outpatients with anorexia nervosa","volume":"165","author":"Miller","year":"2005","journal-title":"Arch. Intern. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1056\/NEJM200004273421707","article-title":"Evaluation of abnormal liver-enzyme results in asymptomatic patients","volume":"342","author":"Pratt","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kheloufi, M., Boulanger, C.M., Durand, F., and Rautou, P.E. (2014). Liver autophagy in anorexia nervosa and acute liver injury. Biomed. Res. Int., 2014.","DOI":"10.1155\/2014\/701064"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1101\/gad.1599207","article-title":"Autophagy: Process and function","volume":"21","author":"Mizushima","year":"2007","journal-title":"Genes. Dev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1002\/hep.27597","article-title":"Autosis occurs in the liver of patients with severe anorexia nervosa","volume":"62","author":"Kheloufi","year":"2015","journal-title":"Hepatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1016\/j.celrep.2017.05.020","article-title":"ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis","volume":"19","author":"Sheldon","year":"2017","journal-title":"Cell Rep."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Gabloffsky, T., Gill, S., Staffeld, A., Salomon, R., Power Guerra, N., Joost, S., Hawlitschka, A., Kipp, M., and Frintrop, L. (2022). Food Restriction in Mice Induces Food-Anticipatory Activity and Circadian-Rhythm-Related Activity Changes. Nutrients, 14.","DOI":"10.3390\/nu14245252"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"274","DOI":"10.3109\/15622975.2016.1173725","article-title":"Memory impairment is associated with the loss of regular oestrous cycle and plasma oestradiol levels in an activity-based anorexia animal model","volume":"17","author":"Paulukat","year":"2016","journal-title":"World J. Biol. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.jneumeth.2017.09.018","article-title":"Establishment of a chronic activity-based anorexia rat model","volume":"293","author":"Frintrop","year":"2018","journal-title":"J. Neurosci. Methods"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41398-019-0493-7","article-title":"The reduction of astrocytes and brain volume loss in anorexia nervosa-the impact of starvation and refeeding in a rodent model","volume":"9","author":"Frintrop","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Staffeld, A., Gill, S., Zimmermann, A., Boge, N., Schuster, K., Lang, S., Kipp, M., Palme, R., and Frintrop, L. (2023). Establishment of a Murine Chronic Anorexia Nervosa Model. Cells, 12.","DOI":"10.3390\/cells12131710"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1097\/YCO.0000000000000278","article-title":"Epidemiology of eating disorders in Europe: Prevalence, incidence, comorbidity, course, consequences, and risk factors","volume":"29","author":"Mustelin","year":"2016","journal-title":"Curr. Opin. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s00418-019-01786-4","article-title":"Continuous cuprizone intoxication allows active experimental autoimmune encephalomyelitis induction in C57BL\/6 mice","volume":"152","author":"Yakimov","year":"2019","journal-title":"Histochem. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zhan, J., Yakimov, V., Ruhling, S., Fischbach, F., Nikolova, E., Joost, S., Kaddatz, H., Greiner, T., Frenz, J., and Holzmann, C. (2019). High Speed Ventral Plane Videography as a Convenient Tool to Quantify Motor Deficits during Pre-Clinical Experimental Autoimmune Encephalomyelitis. Cells, 8.","DOI":"10.3390\/cells8111439"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1080\/15622975.2016.1273552","article-title":"Reduced astrocyte density underlying brain volume reduction in activity-based anorexia rats","volume":"19","author":"Frintrop","year":"2018","journal-title":"World J. Biol. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jappgeo.2016.06.016","article-title":"Rolling ball algorithm as a multitask filter for terrain conductivity measurements","volume":"132","author":"Rashed","year":"2016","journal-title":"J. Appl. Geophys."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"315","DOI":"10.14740\/jmc3713","article-title":"Two Acute Liver Injuries in a Patient with Malnutrition","volume":"12","author":"Su","year":"2021","journal-title":"J. Med. Cases"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1111\/hepr.13792","article-title":"Value of liver biopsy in anorexia nervosa-related transaminitis: A case study and literature review","volume":"52","author":"Faragalla","year":"2022","journal-title":"Hepatol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1007\/s40519-020-01060-w","article-title":"Liver disease in obesity and underweight: The two sides of the coin. A narrative review","volume":"26","author":"Risi","year":"2021","journal-title":"Eat. Weight. Disord."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1007\/s00535-006-1845-7","article-title":"Severe steatosis resulted from anorexia nervosa leading to fatal hepatic failure","volume":"41","author":"Sakada","year":"2006","journal-title":"J. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1007\/s10620-017-4766-9","article-title":"Hepatic Complications of Anorexia Nervosa","volume":"62","author":"Rosen","year":"2017","journal-title":"Dig. Dis. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1093\/jn\/130.1.104","article-title":"Apoptosis and cell proliferation are involved in the initiation of liver carcinogenesis by a subnecrogenic dose of diethylnitrosamine in refed rats","volume":"130","author":"Tessitore","year":"2000","journal-title":"J. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7233","DOI":"10.1038\/s41598-018-25548-9","article-title":"Alterations of proteome, mitochondrial dynamic and autophagy in the hypothalamus during activity-based anorexia","volume":"8","author":"Nobis","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1091\/mbc.e03-09-0704","article-title":"In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker","volume":"15","author":"Mizushima","year":"2004","journal-title":"Mol. Biol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"C11","DOI":"10.1083\/jcb.35.2.C11","article-title":"Participation of lysosomes in cellular autophagy induced in rat liver by glucagon","volume":"35","author":"Deter","year":"1967","journal-title":"J. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1101\/gad.305441.117","article-title":"Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation","volume":"31","author":"Ruan","year":"2017","journal-title":"Genes. Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1146\/annurev.nu.07.070187.002543","article-title":"Intracellular protein catabolism and its control during nutrient deprivation and supply","volume":"7","author":"Mortimore","year":"1987","journal-title":"Annu. Rev. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1126\/science.1193497","article-title":"Autophagy and metabolism","volume":"330","author":"Rabinowitz","year":"2010","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s00421-009-1121-7","article-title":"Lipid peroxidation and antioxidant status in rat: Effect of food restriction and wheel running","volume":"107","author":"Filaire","year":"2009","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"691881","DOI":"10.3389\/fnagi.2021.691881","article-title":"The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Neurodegeneration in Parkinson\u2019s Disease","volume":"13","author":"Ren","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1080\/15548627.2015.1091141","article-title":"ER stress: Autophagy induction, inhibition and selection","volume":"11","author":"Rashid","year":"2015","journal-title":"Autophagy"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1002\/(SICI)1098-108X(199611)20:3<325::AID-EAT13>3.0.CO;2-Z","article-title":"Abnormal liver enzymes in outpatients with eating disorders","volume":"20","author":"Mickley","year":"1996","journal-title":"Int. J. Eat. Disord."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1002\/eat.20432","article-title":"Cholinesterase and other serum liver enzymes in underweight outpatients with eating disorders","volume":"40","author":"Montagnese","year":"2007","journal-title":"Int. J. Eat. Disord."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.jpeds.2008.01.036","article-title":"Prevalence and predictors of abnormal liver enzymes in young women with anorexia nervosa","volume":"153","author":"Fong","year":"2008","journal-title":"J. Pediatr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.2169\/internalmedicine.47.0824","article-title":"Hepatocellular injuries observed in patients with an eating disorder prior to nutritional treatment","volume":"47","author":"Tsukamoto","year":"2008","journal-title":"Intern. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.jpeds.2014.10.048","article-title":"Associations of elevated liver enzymes among hospitalized adolescents with anorexia nervosa","volume":"166","author":"Nagata","year":"2015","journal-title":"J. Pediatr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s11739-019-02227-9","article-title":"Liver alterations in anorexia nervosa are not caused by insulin resistance","volume":"15","author":"Fanin","year":"2019","journal-title":"Intern. Emerg. Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Cuntz, U., and Voderholzer, U. (2022). Liver Damage Is Related to the Degree of Being Underweight in Anorexia Nervosa and Improves Rapidly with Weight Gain. Nutrients, 14.","DOI":"10.3390\/nu14122378"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1002\/eat.1096","article-title":"Anorexia nervosa, diabetes mellitus, brain atrophy, and fatty liver","volume":"30","author":"Pinto","year":"2001","journal-title":"Int. J. Eat. Disord."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.nut.2006.01.003","article-title":"Severe acute liver damage in anorexia nervosa: Two case reports","volume":"22","author":"Alfano","year":"2006","journal-title":"Nutrition"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1002\/eat.22073","article-title":"Elevation of liver function tests in severe anorexia nervosa","volume":"46","author":"Harris","year":"2013","journal-title":"Int. J. Eat Disord."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2013\/749169","article-title":"Severe Starvation-Induced Hepatocyte Autophagy as a Cause of Acute Liver Injury in Anorexia Nervosa: A Case Report","volume":"2013","author":"Restellini","year":"2013","journal-title":"Case Rep. Hepatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1097\/MEG.0000000000000030","article-title":"Reversible severe hepatitis in anorexia nervosa: A case report and overview","volume":"26","author":"Ramsoekh","year":"2014","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3107","DOI":"10.2169\/internalmedicine.6855-20","article-title":"Gastroesophageal Varices and Hyperplastic Nodules of the Liver in a Patient with Anorexia Nervosa","volume":"60","author":"Takata","year":"2021","journal-title":"Intern. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"121","DOI":"10.2739\/kurumemedj.MS6723011","article-title":"Pathogenesis of Severe Liver Injury in Patients with Anorexia Nervosa: A Report of Two Cases and a Literature Review","volume":"67","author":"Sakata","year":"2020","journal-title":"Kurume Med. J."},{"key":"ref_52","first-page":"003675","article-title":"A Hepatic Manifestation of Anorexia Nervosa","volume":"10","author":"Wallace","year":"2023","journal-title":"Eur. J. Case Rep. Intern. Med."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/8\/1191\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:29:12Z","timestamp":1760106552000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/8\/1191"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,17]]},"references-count":52,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["nu16081191"],"URL":"https:\/\/doi.org\/10.3390\/nu16081191","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,17]]}}}