{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:18:44Z","timestamp":1791559124549,"version":"4.3.4"},"reference-count":49,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T00:00:00Z","timestamp":1722470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Grants-in-Aid for Scientific Research JSPS KAKENHI","doi-asserted-by":"publisher","award":["25460988"],"award-info":[{"award-number":["25460988"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Grants-in-Aid for Scientific Research JSPS KAKENHI","doi-asserted-by":"publisher","award":["16K09352"],"award-info":[{"award-number":["16K09352"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Grants-in-Aid for Scientific Research JSPS KAKENHI","doi-asserted-by":"publisher","award":["19K08465"],"award-info":[{"award-number":["19K08465"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>More effective treatments for hepatitis viral infections have led to a reduction in the incidence of liver cirrhosis. A high-fat diet can lead to chronic hepatitis and liver fibrosis, but the effects of lipid intake on liver disease status, including hepatitis C virus and alcohol, after elimination of the cause are unclear. To investigate the effects, we used a rat cirrhosis model and a high-fat diet in this study. Male Wistar rats were administered carbon tetrachloride for 5 weeks. At 12 weeks of age, one group was sacrificed. The remaining rats were divided into four groups according to whether or not they were administered carbon tetrachloride for 5 weeks, and whether they were fed a high-fat diet or control diet. At 12 weeks of age, liver fibrosis became apparent and then improved in the groups where carbon tetrachloride was discontinued, while it worsened in the groups where carbon tetrachloride was continued. Liver fibrosis was notable in both the carbon tetrachloride discontinuation and continuation groups due to the administration of a high-fat diet. In addition, liver precancerous lesions were observed in all groups, and tumor size and multiplicity were higher in the high-fat diet-fed groups. The expression of genes related to inflammation and lipogenesis were upregulated in rats fed a high-fat diet compared to their controls. The results suggest that a high-fat diet worsens liver fibrosis and promotes liver carcinogenesis, presumably through enhanced inflammation and lipogenesis, even after eliminating the underlying cause of liver cirrhosis.<\/jats:p>","DOI":"10.3390\/nu16152506","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T08:14:46Z","timestamp":1722500086000},"page":"2506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["High-Fat Diet Delays Liver Fibrosis Recovery and Promotes Hepatocarcinogenesis in Rat Liver Cirrhosis Model"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6626-7320","authenticated-orcid":false,"given":"Daisuke","family":"Taguchi","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2471-090X","authenticated-orcid":false,"given":"Yohei","family":"Shirakami","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyasu","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihide","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6373-260X","authenticated-orcid":false,"given":"Takao","family":"Miwa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Kubota","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Ibuka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1151-2058","authenticated-orcid":false,"given":"Masahito","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s00535-018-1503-x","article-title":"Efficacy and safety of sofosbuvir-velpatasvir with or without ribavirin in HCV-infected Japanese patients with decompensated cirrhosis: An open-label phase 3 trial","volume":"54","author":"Takehara","year":"2019","journal-title":"J. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s00535-019-01645-y","article-title":"Transition in the etiology of liver cirrhosis in Japan: A nationwide survey","volume":"55","author":"Enomoto","year":"2020","journal-title":"J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1007\/s10620-019-05537-2","article-title":"Disease Burden of Hepatocellular Carcinoma: A Global Perspective","volume":"64","author":"Sayiner","year":"2019","journal-title":"Dig. Dis. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S79","DOI":"10.1016\/j.jhep.2014.07.010","article-title":"Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma","volume":"61","author":"Hoshida","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14","DOI":"10.5152\/tjg.2018.17330","article-title":"Liver fibrosis","volume":"29","author":"Aydin","year":"2018","journal-title":"Turk. J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Delgado, M.E., Cardenas, B.I., Farran, N., and Fernandez, M. (2021). Metabolic Reprogramming of Liver Fibrosis. Cells, 10.","DOI":"10.3390\/cells10123604"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.amjmed.2020.08.010","article-title":"The Impact of Nonalcoholic Fatty Liver Disease in Primary Care: A Population Health Perspective","volume":"134","author":"Dokmak","year":"2021","journal-title":"Am. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"157","DOI":"10.3350\/cmh.2020.0176","article-title":"Obesity and the risk of primary liver cancer: A systematic review and meta-analysis","volume":"27","author":"Sohn","year":"2021","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"755","DOI":"10.4254\/wjh.v15.i6.755","article-title":"Treatment of liver fibrosis: Past, current, and future","volume":"15","author":"Zhang","year":"2023","journal-title":"World J. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/S1542-3565(05)00017-0","article-title":"Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis","volume":"3","author":"Muto","year":"2005","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Iwasa, M., Kobayashi, Y., Mifuji-Moroka, R., Hara, N., Miyachi, H., Sugimoto, R., Tanaka, H., Fujita, N., Gabazza, E.C., and Takei, Y. (2013). Branched-chain amino acid supplementation reduces oxidative stress and prolongs survival in rats with advanced liver cirrhosis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070309"},{"key":"ref_13","first-page":"CD001939","article-title":"Branched-chain amino acids for people with hepatic encephalopathy","volume":"5","author":"Gluud","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/s00535-021-01788-x","article-title":"Evidence-based clinical practice guidelines for Liver Cirrhosis 2020","volume":"56","author":"Yoshiji","year":"2021","journal-title":"J. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1002\/hep.32049","article-title":"Malnutrition, Frailty, and Sarcopenia in Patients with Cirrhosis: 2021 Practice Guidance by the American Association for the Study of Liver Diseases","volume":"74","author":"Lai","year":"2021","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s00394-012-0301-0","article-title":"Garlic-derived S-allylmercaptocysteine is a hepato-protective agent in non-alcoholic fatty liver disease in vivo animal model","volume":"52","author":"Xiao","year":"2013","journal-title":"Eur. J. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1186\/2193-1801-2-690","article-title":"(\u2212)-Epigallocatechin-3-gallate suppresses hepatic preneoplastic lesions developed in a novel rat model of non-alcoholic steatohepatitis","volume":"2","author":"Sumi","year":"2013","journal-title":"Springerplus"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"33972","DOI":"10.18632\/oncotarget.26119","article-title":"Inhibitory effects of pentoxifylline on inflammation-related tumorigenesis in rat colon","volume":"9","author":"Shirakami","year":"2018","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.3892\/mmr.2015.3646","article-title":"Leptin modulates the expression of catabolic genes in rat nucleus pulposus cells through the mitogen-activated protein kinase and Janus kinase 2\/signal transducer and activator of transcription 3 pathways","volume":"12","author":"Miao","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4829","DOI":"10.3390\/nu7064829","article-title":"Protective Effect of the Total Saponins from Rosa laevigata Michx Fruit against Carbon Tetrachloride-Induced Liver Fibrosis in Rats","volume":"7","author":"Dong","year":"2015","journal-title":"Nutrients"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.canlet.2013.08.031","article-title":"Non-alcoholic steatohepatitis and preneoplastic lesions develop in the liver of obese and hypertensive rats: Suppressing effects of EGCG on the development of liver lesions","volume":"342","author":"Kochi","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1111\/j.1872-034X.2009.00616.x","article-title":"Insulin resistance raises the risk for recurrence of stage I hepatocellular carcinoma after curative radiofrequency ablation in hepatitis C virus-positive patients: A prospective, case series study","volume":"40","author":"Imai","year":"2010","journal-title":"Hepatol. Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Phoolchund, A.G.S., and Khakoo, S.I. (2024). MASLD and the Development of HCC: Pathogenesis and Therapeutic Challenges. Cancers, 16.","DOI":"10.3390\/cancers16020259"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.jhep.2016.05.005","article-title":"A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer","volume":"65","author":"Asgharpour","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"G174","DOI":"10.1152\/ajpgi.00041.2019","article-title":"Comparison of murine steatohepatitis models identifies a dietary intervention with robust fibrosis, ductular reaction, and rapid progression to cirrhosis and cancer","volume":"318","author":"Wei","year":"2020","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_26","first-page":"304","article-title":"Liver fibrosis associated with adipose tissue and liver inflammation in an obesity model","volume":"76","author":"Setyaningsih","year":"2021","journal-title":"Med. J. Malays."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Farooq, M., Hameed, H., Dimanche-Boitrel, M.T., Piquet-Pellorce, C., Samson, M., and Le Seyec, J. (2022). Switching to Regular Diet Partially Resolves Liver Fibrosis Induced by High-Fat, High-Cholesterol Diet in Mice. Nutrients, 14.","DOI":"10.3390\/nu14020386"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1053\/j.gastro.2003.08.032","article-title":"Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]","volume":"125","author":"Hui","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1111\/cas.12700","article-title":"Differential reactivation of fetal\/neonatal genes in mouse liver tumors induced in cirrhotic and non-cirrhotic conditions","volume":"106","author":"Chen","year":"2015","journal-title":"Cancer Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1007\/s11356-021-15689-2","article-title":"Metronidazole enhances steatosis-related early-stage hepatocarcinogenesis in high fat diet-fed rats through DNA double-strand breaks and modulation of autophagy","volume":"29","author":"Eguchi","year":"2022","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"565","DOI":"10.2131\/jts.44.565","article-title":"Immunohistochemical expression of autophagosome markers LC3 and p62 in preneoplastic liver foci in high fat diet-fed rats","volume":"44","author":"Masuda","year":"2019","journal-title":"J. Toxicol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.cell.2009.12.052","article-title":"Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression","volume":"140","author":"Park","year":"2010","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5651","DOI":"10.1002\/cncr.24687","article-title":"Metabolic syndrome and hepatocellular carcinoma: Two growing epidemics with a potential link","volume":"115","author":"Siegel","year":"2009","journal-title":"Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.gde.2008.02.003","article-title":"Brick by brick: Metabolism and tumor cell growth","volume":"18","author":"Deberardinis","year":"2008","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Drury, J., Geisen, M.E., Tessmann, J.W., Rychahou, P.G., Kelson, C.O., He, D., Wang, C., Evers, B.M., and Zaytseva, Y.Y. (2024). Overexpression of Fatty Acid Synthase Upregulates Glutamine-Fructose-6-Phosphate Transaminase 1 and O-Linked N-Acetylglucosamine Transferase to Increase O-GlcNAc Protein Glycosylation and Promote Colorectal Cancer Growth. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25094883"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"100987","DOI":"10.1016\/j.gendis.2023.04.022","article-title":"The roles and mechanisms of SREBP1 in cancer development and drug response","volume":"11","author":"He","year":"2024","journal-title":"Genes Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1097\/CEJ.0000000000000172","article-title":"Pentoxifylline prevents nonalcoholic steatohepatitis-related liver pre-neoplasms by inhibiting hepatic inflammation and lipogenesis","volume":"25","author":"Shirakami","year":"2016","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3748\/wjg.v22.i1.394","article-title":"Chemoprevention of obesity-related liver carcinogenesis by using pharmaceutical and nutraceutical agents","volume":"22","author":"Sakai","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.3390\/nu5051544","article-title":"Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease","volume":"5","author":"Gaggini","year":"2013","journal-title":"Nutrients"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/j.cmet.2021.06.005","article-title":"Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication","volume":"33","author":"Loft","year":"2021","journal-title":"Cell Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"998","DOI":"10.3390\/curroncol31020075","article-title":"Insulin Resistance: The Increased Risk of Cancers","volume":"31","author":"Szablewski","year":"2024","journal-title":"Curr. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"118944","DOI":"10.1016\/j.lfs.2020.118944","article-title":"High sucrose diet attenuates oxidative stress, inflammation and liver injury in thioacetamide-induced liver cirrhosis","volume":"267","author":"Paulino","year":"2021","journal-title":"Life Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e1978","DOI":"10.1002\/cnr2.1978","article-title":"Identifying the predictive role and the related drugs of oxidative stress genes in the hepatocellular carcinoma","volume":"7","author":"Nie","year":"2024","journal-title":"Cancer Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.oraloncology.2013.09.011","article-title":"Oxidative and antioxidative mechanisms in oral cancer and precancer: A review","volume":"50","author":"Choudhari","year":"2014","journal-title":"Oral Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Jimenez-Cortegana, C., Garcia-Galey, A., Tami, M., Del Pino, P., Carmona, I., Lopez, S., Alba, G., and Sanchez-Margalet, V. (2021). Role of Leptin in Non-Alcoholic Fatty Liver Disease. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070762"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e2306776121","DOI":"10.1073\/pnas.2306776121","article-title":"A high-fat diet promotes cancer progression by inducing gut microbiota-mediated leucine production and PMN-MDSC differentiation","volume":"121","author":"Chen","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Li, J., Zhang, H., and Dai, Z. (2021). Cancer Treatment with the Ketogenic Diet: A Systematic Review and Meta-analysis of Animal Studies. Front. Nutr., 8.","DOI":"10.3389\/fnut.2021.594408"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s10238-021-00710-2","article-title":"The use of ketogenic diets in cancer patients: A systematic review","volume":"21","author":"Huebner","year":"2021","journal-title":"Clin. Exp. Med."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Goswami, S., Zhang, Q., Celik, C.E., Reich, E.M., and Yilmaz, \u00d6.H. (2023). Dietary fat and lipid metabolism in the tumor microenvironment. Biochim. Biophys. Acta Rev. Cancer, 1878.","DOI":"10.1016\/j.bbcan.2023.188984"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/15\/2506\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:27:42Z","timestamp":1760110062000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/15\/2506"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,1]]},"references-count":49,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["nu16152506"],"URL":"https:\/\/doi.org\/10.3390\/nu16152506","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,1]]}}}