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Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet

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العنوان: Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet
المؤلفون: ffolliott M. Fisher, Eleftheria Maratos-Flier, Imad Nasser, Suzanne Chan, Garima Singhal, Yong Ma, Gaurav Kumar, Hilde Vardeh, Jeffrey S. Flier
المصدر: Molecular Metabolism, Vol 13, Iss, Pp 56-66 (2018)
Molecular Metabolism
بيانات النشر: Elsevier, 2018.
سنة النشر: 2018
مصطلحات موضوعية: Liver Cirrhosis, Male, 0301 basic medicine, medicine.medical_specialty, lcsh:Internal medicine, Carcinoma, Hepatocellular, FGF21, Cirrhosis, Hepatocellular carcinoma, Liver fibrosis, Fibroblast growth factor 21, Diet, High-Fat, Fibroblast growth factor, Mice, 03 medical and health sciences, Non-alcoholic Fatty Liver Disease, Fibrosis, Internal medicine, Nonalcoholic fatty liver disease, medicine, Animals, Obesity, Nonalcoholic steatohepatitis, lcsh:RC31-1245, Molecular Biology, Mice, Knockout, business.industry, Liver Neoplasms, Fatty liver, Cell Biology, medicine.disease, High fat high sucrose diet, Fibroblast Growth Factors, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Liver, Original Article, Steatohepatitis, business
الوصف: Objective Non-alcoholic fatty liver (NAFL) associated with obesity is a major cause of liver diseases which can progress to non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Fibroblast growth factor 21 (FGF21) plays an important role in liver metabolism and is also a potential marker for NAFL. Here we aimed to test the effect of FGF21 deficiency on liver pathology in mice consuming a conventional high fat, high sucrose (HFHS) obesogenic diet for up to 52 weeks. Methods C57BL6 WT and FGF21 KO mice were fed a conventional obesogenic diet and were evaluated at 16 and 52 weeks. Evaluation included metabolic assessment, liver pathology, and transcriptomic analysis. Results With consumption of HFHS diet, FGF21 deficient mice (FGF21 KO) develop excess fatty liver within 16 weeks. Hepatic pathology progresses and at 52 weeks FGF21 KO mice show significantly worse fibrosis and 78% of mice develop HCC; in contrast only 6% of WT mice develop HCC. Well differentiated hepatocellular carcinomas in FGF21 KO mice were characterized by expanded hepatic plates, loss of reticulin network, cytologic atypia, and positive immunostaining for glutamine synthetase. Microarray analysis reveals enrichment of several fibroblast growth factor signaling pathways in the tumors. Conclusions In addition to attenuating inflammation and fibrosis in mice under a number of dietary challenges, we show here that FGF21 is required to limit the progression from NAFL to HCC in response to prolonged exposure to an obesogenic diet. The induction of hepatic FGF21 in response to the high fat, high sucrose obesogenic diet may play an important role in limiting progression of liver pathology from NAFL to HCC.
Highlights • FGF21 deficiency in the context of a standard high, fat high sucrose, obesogenic diet increases liver pathology with rapid progression to NASH. • Hepatic pathology in FGF21 KO mice progresses to hepatocellular carcinoma. • Microarray analysis of the tumors reveals enrichment of several fibroblast growth factor signaling pathways. • Results noted here are similar to increased rates of progressive NAFLD in obese populations consuming Western style diets.
اللغة: English
تدمد: 2212-8778
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8eba62e51d24a949edc8b891c5a06666
http://www.sciencedirect.com/science/article/pii/S2212877818301091
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....8eba62e51d24a949edc8b891c5a06666
قاعدة البيانات: OpenAIRE
الوصف
تدمد:22128778