{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T16:49:03Z","timestamp":1780678143544,"version":"3.54.1"},"reference-count":39,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,3,28]],"date-time":"2019-03-28T00:00:00Z","timestamp":1553731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Atherosclerosis and nonalcoholic fatty liver disease (NAFLD) are frequent causes of death in the Western countries. Recently, it has been shown that autophagy dysfunction plays an important role in the pathogenesis of both atherosclerosis and NAFLD; thus, activators of autophagy might be useful for novel therapeutic interventions. Trehalose\u2014a naturally occuring disaccharide present in plants, bacteria, fungi, insects, and certain types of shrimps\u2014is a known inducer of autophagy. However, according to the literature, its anti-atherosclerotic and anti-steatotic potential seem to depend on the experimental setting. The aim of our study was to comprehensively describe the influence of a prolonged treatment with orally administered trehalose on the development of atherosclerotic lesions and hepatic steatosis in apolipoprotein E knockout (apoE\u2212\/\u2212) mice in an experimental set up reflecting both moderate and severe proatherogenic conditions: male apoE\u2212\/\u2212 mice on a chow diet (CD) and female apoE\u2212\/\u2212 mice fed with a high-fat diet (HFD). We found that exogenous trehalose inhibited atherosclerosis and attenuated hepatic steatosis in apoE\u2212\/\u2212 mice. Such effects of trehalose were not associated with changes of plasma cholesterol, low-density lipoproteins (LDL), or high-density lipoproteins (HDL). Moreover, the anti-steatotic action of trehalose in the liver was associated with the induction of autophagy. The exact molecular mechanisms of both the anti-atherosclerotic action of trehalose and its inhibitory effect on liver steatosis require further clarification.<\/jats:p>","DOI":"10.3390\/ijms20071552","type":"journal-article","created":{"date-parts":[[2019,3,29]],"date-time":"2019-03-29T03:38:52Z","timestamp":1553830732000},"page":"1552","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["The Influence of Trehalose on Atherosclerosis and Hepatic Steatosis in Apolipoprotein E Knockout Mice"],"prefix":"10.3390","volume":"20","author":[{"given":"Aneta","family":"Stachowicz","sequence":"first","affiliation":[{"name":"Chair of Pharmacology, Jagiellonian University Medical College, 31-531 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7370-9879","authenticated-orcid":false,"given":"Anna","family":"Wi\u015bniewska","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Jagiellonian University Medical College, 31-531 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6107-0115","authenticated-orcid":false,"given":"Katarzyna","family":"Ku\u015b","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Jagiellonian University Medical College, 31-531 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kiepura","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Jagiellonian University Medical College, 31-531 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"G\u0119bska","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Jagiellonian University Medical College, 31-531 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariusz","family":"Gajda","sequence":"additional","affiliation":[{"name":"Department of Histology, Jagiellonian University Medical College, 33-332 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Bia\u0142as","sequence":"additional","affiliation":[{"name":"Chair of Pathomorphology, Jagiellonian University Medical College, 31-531 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5970-238X","authenticated-orcid":false,"given":"Justyna","family":"Toto\u0144-\u017bura\u0144ska","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Jagiellonian University Medical College, 31-531 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamila","family":"Stachyra","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Jagiellonian University Medical College, 31-531 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7575-2184","authenticated-orcid":false,"given":"Maciej","family":"Suski","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Jagiellonian University Medical College, 31-531 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacek","family":"Jawie\u0144","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Jagiellonian University Medical College, 31-531 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryszard","family":"Korbut","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Jagiellonian University Medical College, 31-531 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafa\u0142","family":"Olszanecki","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Jagiellonian University Medical College, 31-531 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1161\/CIRCULATIONAHA.109.849166","article-title":"Cardiovascular risk prediction: Basic concepts, current status, and future directions","volume":"121","year":"2010","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1161\/CIRCRESAHA.114.302721","article-title":"Mechanisms of plaque formation and rupture","volume":"114","author":"Bentzon","year":"2014","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1253\/circj.CJ-09-0706","article-title":"Inflammation in atherosclerosis: Transition from theory to practice","volume":"74","author":"Libby","year":"2010","journal-title":"Circ. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1464-5491.2007.02025.x","article-title":"Non-alcoholic fatty liver disease, the metabolic syndrome and the risk of cardiovascular disease: The plot thickens","volume":"24","author":"Targher","year":"2007","journal-title":"Diabet. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1126\/science.1204265","article-title":"Human fatty liver disease: Old questions and new insights","volume":"332","author":"Cohen","year":"2011","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1038\/aps.2015.87","article-title":"The roles of macrophage autophagy in atherosclerosis","volume":"37","author":"Shao","year":"2016","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1007\/s00726-017-2429-y","article-title":"Relevance of autophagy to fatty liver diseases and potential therapeutic applications","volume":"49","author":"Yan","year":"2017","journal-title":"Amino Acids"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"17R","DOI":"10.1093\/glycob\/cwg047","article-title":"New insights on trehalose: A multifunctional molecule","volume":"13","author":"Elbein","year":"2003","journal-title":"Glycobiology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.cmet.2012.01.022","article-title":"Macrophage autophagy plays a protective role in advanced atherosclerosis","volume":"15","author":"Liao","year":"2012","journal-title":"Cell Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.jhep.2013.01.011","article-title":"Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice","volume":"58","author":"Lin","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5641","DOI":"10.1074\/jbc.M609532200","article-title":"Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein","volume":"282","author":"Sarkar","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1093\/glycob\/cwu125","article-title":"Insect trehalase: Physiological significance and potential applications","volume":"25","author":"Shukla","year":"2015","journal-title":"Glycobiology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3125","DOI":"10.1242\/jeb.01133","article-title":"Role of trehalose phosphate synthase and trehalose during hypoxia: From flies to mammals","volume":"207","author":"Chen","year":"2004","journal-title":"J. Exp. Biol."},{"key":"ref_14","unstructured":"Food and Agriculture Organization, and World Health Organization (2001). Expert Committee on Food Additives Evaluation of Certain Food Additives and Contaminants, World Health Organization."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"ra21","DOI":"10.1126\/scisignal.aac5472","article-title":"Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis","volume":"9","author":"DeBosch","year":"2016","journal-title":"Sci Signal"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.nutres.2010.10.009","article-title":"Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance","volume":"30","author":"Arai","year":"2010","journal-title":"Nutr. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1093\/hmg\/ddi422","article-title":"Trehalose reduces aggregate formation and delays pathology in a transgenic mouse model of oculopharyngeal muscular dystrophy","volume":"15","author":"Davies","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/nm985","article-title":"Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease","volume":"10","author":"Tanaka","year":"2004","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15750","DOI":"10.1038\/ncomms15750","article-title":"Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis","volume":"8","author":"Sergin","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sahebkar, A., Hatamipour, M., and Tabatabaei, S.A. (2018). Trehalose administration attenuates atherosclerosis in rabbits fed a high-fat diet. J. Cell. Biochem.","DOI":"10.1002\/jcb.28221"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.jprot.2012.08.015","article-title":"Proteomic analysis of liver mitochondria of apolipoprotein E knockout mice treated with metformin","volume":"77","author":"Stachowicz","year":"2012","journal-title":"J Proteom."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"338","DOI":"10.2174\/138161208783497769","article-title":"Apolipoprotein E knockout models","volume":"14","author":"Kolovou","year":"2008","journal-title":"Curr. Pharm. Des."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1161\/CIRCRESAHA.111.261388","article-title":"Aging and atherosclerosis: Mechanisms, functional consequences, and potential therapeutics for cellular senescence","volume":"111","author":"Wang","year":"2012","journal-title":"Circ. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"712","DOI":"10.5551\/jat.3541","article-title":"Sex as a profound modifier of atherosclerotic lesion development in apolipoprotein E-deficient mice with different genetic backgrounds","volume":"17","author":"Surra","year":"2010","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"12931","DOI":"10.1038\/srep12931","article-title":"Seven weeks of Western diet in apolipoprotein-E-deficient mice induce metabolic syndrome and non-alcoholic steatohepatitis with liver fibrosis","volume":"5","author":"Schierwagen","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1080\/15548627.2018.1434373","article-title":"TFEB and trehalose drive the macrophage autophagy-lysosome system to protect against atherosclerosis","volume":"14","author":"Evans","year":"2018","journal-title":"Autophagy"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1161\/ATVBAHA.111.224899","article-title":"Autophagy in atherosclerosis: A potential drug target for plaque stabilization","volume":"31","author":"Schrijvers","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"fs2","DOI":"10.1126\/scisignal.aaf1937","article-title":"Mystery solved: Trehalose kickstarts autophagy by blocking glucose transport","volume":"9","author":"Mardones","year":"2016","journal-title":"Sci. Signal."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"393","DOI":"10.3177\/jnsv.59.393","article-title":"Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance in mice with established obesity","volume":"59","author":"Arai","year":"2013","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.jnutbio.2017.02.022","article-title":"Trehalose supplementation reduces hepatic endoplasmic reticulum stress and inflammatory signaling in old mice","volume":"45","author":"Pagliassotti","year":"2017","journal-title":"J. Nutr. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"380","DOI":"10.3177\/jnsv.62.380","article-title":"Daily Intake of Trehalose Is Effective in the Prevention of Lifestyle-Related Diseases in Individuals with Risk Factors for Metabolic Syndrome","volume":"62","author":"Mizote","year":"2016","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"93R","DOI":"10.1093\/glycob\/cwg090","article-title":"Glycosidase inhibitors: Update and perspectives on practical use","volume":"13","author":"Asano","year":"2003","journal-title":"Glycobiology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/S0278-6915(02)00011-X","article-title":"Trehalose: A review of properties, history of use and human tolerance, and results of multiple safety studies","volume":"40","author":"Richards","year":"2002","journal-title":"Food Chem. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1080\/00365521.1973.12096765","article-title":"Meyer zum Bueschenfelde, null Trehalose tolerance test. Its value as a test for malabsorption","volume":"8","author":"Bergoz","year":"1973","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.bbrc.2016.10.072","article-title":"Short chain fatty acids induce UCP2-mediated autophagy in hepatic cells","volume":"480","author":"Iannucci","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"660","DOI":"10.5551\/jat.RV17006","article-title":"Are Short Chain Fatty Acids in Gut Microbiota Defensive Players for Inflammation and Atherosclerosis?","volume":"24","author":"Ohira","year":"2017","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose translation from animal to human studies revisited","volume":"22","author":"Nihal","year":"2008","journal-title":"FASEB J."},{"key":"ref_38","first-page":"247","article-title":"The effect of doxycycline on atherogenesis in apoE-knockout mice","volume":"62","author":"Pawlowska","year":"2011","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e001329","DOI":"10.1161\/JAHA.114.001329","article-title":"Mitochondrial aldehyde dehydrogenase activation by alda-1 inhibits atherosclerosis and attenuates hepatic steatosis in apolipoprotein e-knockout mice","volume":"3","author":"Stachowicz","year":"2014","journal-title":"J. Am. Heart Assoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1552\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:41:06Z","timestamp":1760186466000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1552"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,28]]},"references-count":39,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["ijms20071552"],"URL":"https:\/\/doi.org\/10.3390\/ijms20071552","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,28]]}}}