{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T18:05:28Z","timestamp":1776103528683,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG)","doi-asserted-by":"publisher","award":["RI 2695\/1-3"],"award-info":[{"award-number":["RI 2695\/1-3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The Carbohydrate-Responsive Element-Binding Protein (ChREBP) is a glucose-sensitive transcription factor that regulates the carbohydrate and lipid metabolism. We investigated its cell-type-specific role in hepatocarcinogenesis using a chemically induced mouse model. Additionally, we examined the functions of its isoforms, ChREBP\u03b1 and ChREBP\u03b2. After the diethylnitrosamine (DEN) administration, we analyzed hepatocellular adenomas and carcinomas in systemic ChREBP-knockout (KO), hepatocyte-specific ChREBP-KO (L-KO), and wildtype (WT) mice at 4, 12, and 36 weeks using histology, morphometry, proliferation measurements, immunohistochemistry, a Western blot, and a quantitative PCR. Tumors developed 36 weeks after the DEN administration in 27% of WT mice but less frequently in KO (18%) and L-KO (9%) mice. However, preneoplastic foci were less common in KO mice but not in L-KO mice (39% vs. 9%; p &lt; 0.05). L-KO hepatocytes exhibited lower proliferation, while KO tumors showed the downregulation of AKT\/mTOR signaling, glycolysis, and lipogenesis compared to WT tumors. Our results showed that the liver-specific loss of ChREBP\u03b1, while ChREBP\u03b2 remained active, significantly reduced the tumor progression, suggesting an oncogenic role for ChREBP\u03b1. In contrast, the systemic knockout of both ChREBP\u03b1 and ChREBP\u03b2 reduced the tumor initiation but did slightly prevent tumor progression, indicating that ChREBP\u03b2 may exert tumor-suppressive functions.<\/jats:p>","DOI":"10.3390\/ijms26146932","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T15:35:51Z","timestamp":1752852951000},"page":"6932","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Carbohydrate-Responsive Element-Binding Protein-Associated Metabolic Changes in Chemically Induced Hepatocarcinogenesis Mouse Model"],"prefix":"10.3390","volume":"26","author":[{"given":"Maren","family":"Engeler","sequence":"first","affiliation":[{"name":"Institute for Pathology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Majedul","family":"Karim","sequence":"additional","affiliation":[{"name":"Institute for Pathology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcel","family":"Gischke","sequence":"additional","affiliation":[{"name":"Institute for Pathology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franziska","family":"Willer","sequence":"additional","affiliation":[{"name":"Institute for Pathology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"Leiner","sequence":"additional","affiliation":[{"name":"Institute for Pathology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Prey","sequence":"additional","affiliation":[{"name":"Institute for Pathology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul Friedrich","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Institute for Pathology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Dombrowski","sequence":"additional","affiliation":[{"name":"Institute for Pathology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Ribback","sequence":"additional","affiliation":[{"name":"Institute for Pathology, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"3","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.jhep.2022.08.021","article-title":"Global burden of primary liver cancer in 2020 and predictions to 2040","volume":"6","author":"Rumgay","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1159\/000449340","article-title":"Molecular Pathogenesis of Hepatocellular Carcinoma","volume":"4","author":"Ho","year":"2016","journal-title":"Liver Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11536","DOI":"10.1158\/0008-5472.CAN-07-1479","article-title":"Hepatocellular carcinoma associated with liver-gender disruption in male mice","volume":"24","author":"Rogers","year":"2007","journal-title":"Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular Carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"113042","DOI":"10.1016\/j.yexcr.2022.113042","article-title":"Preclinical mouse models of hepatocellular carcinoma: An overview and update","volume":"2","author":"Gu","year":"2022","journal-title":"Exp. Cell Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Santos, N.P., Cola\u00e7o, A.A., and Oliveira, P.A. (2017). Animal models as a tool in hepatocellular carcinoma research: A Review. Tumour Biol., 3.","DOI":"10.1177\/1010428317695923"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/0163-7258(96)00062-9","article-title":"N-nitrosodiethylamine mechanistic data and risk assessment: Bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation","volume":"71","author":"Verna","year":"1996","journal-title":"Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1038\/ng1481","article-title":"Application of comparative functional genomics to identify best-fit mouse models to study human cancer","volume":"12","author":"Lee","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.canlet.2004.07.019","article-title":"Oxidative stress in carcinogenesis. Correlation between lipid peroxidation and induction of preneoplastic lesions in rat hepatocarcinogenesis","volume":"217","year":"2005","journal-title":"Cancer Lett."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tang, Q., Wang, Q., Zhang, Q., Lin, S.Y., Zhu, Y., Yang, X., and Guo, A.Y. (2017). Gene expression, regulation of DEN and HBx induced HCC mice models and comparisons of tumor, para-tumor and normal tissues. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3860-x"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.molonc.2013.01.005","article-title":"Mouse models for liver cancer","volume":"7","author":"Bakiri","year":"2013","journal-title":"Mol. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1158\/1541-7786.MCR-18-0313","article-title":"Integrated Genomic Comparison of Mouse Models Reveals Their Clinical Resemblance to Human Liver Cancer","volume":"11","author":"Yim","year":"2018","journal-title":"Mol. Cancer Res."},{"key":"ref_14","first-page":"669","article-title":"Cancer metabolism: Looking forward","volume":"10","author":"Chandel","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s40164-024-00482-x","article-title":"Cancer metabolism and carcinogenesis","volume":"13","author":"Yang","year":"2024","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15597","DOI":"10.1073\/pnas.0405238101","article-title":"Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription","volume":"101","author":"Ishii","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1507\/endocrj.EJ13-0121","article-title":"Recent progress on the role of ChREBP in glucose and lipid metabolism","volume":"5","author":"Iizuka","year":"2013","journal-title":"Endocr. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7281","DOI":"10.1073\/pnas.0401516101","article-title":"Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis","volume":"19","author":"Iizuka","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/j.jhep.2013.01.013","article-title":"Molecular and metabolic changes in human liver clear cell foci resemble the alterations occurring in rat hepatocarcinogenesis","volume":"6","author":"Ribback","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1080\/15384101.2018.1489182","article-title":"Oncogene-dependent addiction to carbohydrate-responsive element binding protein in hepatocellular carcinoma","volume":"12","author":"Ribback","year":"2018","journal-title":"Cell Cycle"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Nuernberger, V., Mortoga, S., Metzendorf, C., Burkert, C., Ehricke, K., Knuth, E., Zimmer, J., Singer, S., Nath, N., and Karim, M. (2021). Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice. Cells, 10.","DOI":"10.3390\/cells10102787"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature10986","article-title":"A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism","volume":"7394","author":"Herman","year":"2012","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11365","DOI":"10.1038\/ncomms11365","article-title":"Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism","volume":"7","author":"Tang","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1038\/ncomms2537","article-title":"De novo lipogenesis in human fat and liver is linked to ChREBP-\u03b2 and metabolic health","volume":"4","author":"Eissing","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E358","DOI":"10.1152\/ajpendo.00027.2006","article-title":"Deficiency of carbohydrate-activated transcription factor ChREBP prevents obesity and improves plasma glucose control in leptin-deficient (ob\/ob) mice","volume":"2","author":"Iizuka","year":"2006","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3577","DOI":"10.1007\/s11010-021-04178-2","article-title":"A lack of ChREBP inhibits mitochondrial cristae formation in brown adipose tissue","volume":"10","author":"Sakiyama","year":"2021","journal-title":"Mol. Cell. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1530\/JOE-19-0498","article-title":"ChREBP-\u03b2 regulates thermogenesis in brown adipose tissue","volume":"3","author":"Wei","year":"2020","journal-title":"J. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104315","DOI":"10.18632\/oncotarget.22234","article-title":"Hepatocellular glycogenotic foci after combined intraportal pancreatic islet transplantation and knockout of the carbohydrate responsive element binding protein in diabetic mice","volume":"61","author":"Ribback","year":"2017","journal-title":"Oncotarget"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"503658","DOI":"10.1016\/j.mrgentox.2023.503658","article-title":"Hepatocyte proliferation activity in untreated rats, measured by immunohistochemical detection of Ki-67: The effect of age on the repeated-dose liver micronucleus assay","volume":"890","author":"Satomoto","year":"2023","journal-title":"Mutat. Res. Genet. Toxicol. Environ. Mutagen."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1016\/j.molmet.2017.07.006","article-title":"Deletion of hepatic carbohydrate response element binding protein (ChREBP) impairs glucose homeostasis and hepatic insulin sensitivity in mice","volume":"11","author":"Jois","year":"2017","journal-title":"Mol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Cigliano, A., Simile, M.M., Vidili, G., Pes, G.M., Dore, M.P., Urigo, F., Cossu, E., Che, L., Feo, C., and Steinmann, S.M. (2024). Fatty Acid Synthase Promotes Hepatocellular Carcinoma Growth via S-Phase Kinase-Associated Protein 2\/p27KIP1 Regulation. Medicina, 7.","DOI":"10.3390\/medicina60071160"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Jia, J., Che, L., Cigliano, A., Wang, X., Peitta, G., Tao, J., Zhong, S., Ribback, S., Evert, M., and Chen, X. (2020). Pivotal Role of Fatty Acid Synthase in c-MYC Driven Hepatocarcinogenesis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms21228467"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1038\/s41467-024-45548-w","article-title":"The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K\/AKT signaling and cancer metabolism","volume":"15","author":"Benichou","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Liu, Y., Wu, H., Mei, Y., Ding, X., Yang, X., Li, C., Deng, M., and Gong, J. (2017). Clinicopathological and prognostic significance of PKM2 protein expression in cirrhotic hepatocellular carcinoma and non-cirrhotic hepatocellular carcinoma. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-14813-y"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1016\/j.chembiol.2017.08.028","article-title":"Targeting Metabolism for Cancer Therapy","volume":"9","author":"Luengo","year":"2017","journal-title":"Cell Chem. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Chang, X., Tian, C., Jia, Y., Cai, Y., and Yan, P. (2023). MLXIPL promotes the migration, invasion, and glycolysis of hepatocellular carcinoma cells by phosphorylation of mTOR. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-10652-5"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.3892\/ol.2016.5110","article-title":"The Ras\/Raf\/MEK\/ERK signaling pathway and its role in the occurrence and development of HCC","volume":"5","author":"Li","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Crowe, A.R., and Yue, W. (2019). Semi-quantitative Determination of Protein Expression using Immunohistochemistry Staining and Analysis: An Integrated Protocol. Bio-Protocol, 24.","DOI":"10.21769\/BioProtoc.3465"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6932\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:12:26Z","timestamp":1760033546000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6932"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,18]]},"references-count":38,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26146932"],"URL":"https:\/\/doi.org\/10.3390\/ijms26146932","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,18]]}}}