Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet.
Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet.
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成纤维细胞生长因子21（FGF21）的缺乏促进了长期肥胖饮食小鼠的肝细胞癌（HCC）。
DOI：
10.1016/j.molmet.2018.03.002
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发表时间：
2018-07
影响因子：
8.1
通讯作者：
Maratos-Flier E
中科院分区：
文献类型：
--
作者：
Singhal G;Kumar G;Chan S;Fisher FM;Ma Y;Vardeh HG;Nasser IA;Flier JS;Maratos-Flier E
非酒精性脂肪肝(NAFL)与肥胖相关，是肝脏疾病的主要原因，可发展为非酒精性脂肪性肝炎、肝硬变和肝细胞癌(HCC)。成纤维细胞生长因子21(FGF21)在肝脏代谢中起重要作用，也是NAFL的潜在标志物。在这里，我们的目的是测试FGF21缺乏对食用高脂肪、高蔗糖(HFHS)肥胖饮食长达52周的小鼠肝脏病理的影响。给C57BL6WT和FGF21KO小鼠饲喂常规饲料，分别在16周和52周进行评价。评估包括代谢评估、肝脏病理和转录本分析。摄入HFHS后，FGF21基因缺陷小鼠(FGF21KO)在16周内出现过度脂肪肝。肝脏病理发生进展，52周时，FGF21KO小鼠表现出明显更严重的纤维化，78%的小鼠发展为肝癌；相比之下，只有6%的WT小鼠发展为肝癌。FGF21KO小鼠高分化肝细胞癌的特点是肝板肿胀、网状蛋白网络缺失、细胞学异型性和谷氨酰胺合成酶免疫染色阳性。微阵列分析显示，肿瘤中有几个成纤维细胞生长因子信号通路的丰富。除了在一些饮食挑战下减轻小鼠的炎症和纤维化之外，我们在这里表明，FGF21是限制从NAFL到肝癌的进展所必需的，以应对长期暴露在肥胖饮食中。高脂肪、高蔗糖饮食诱导肝脏FGF21的表达可能在限制NAFL向肝细胞癌发展的过程中发挥重要作用。FGF21缺乏在标准的高脂肪、高蔗糖、肥胖饮食的背景下会增加肝脏病理，并迅速进展为NASH。FGF21KO小鼠的肝脏病理进展为肝细胞癌。对肿瘤的微阵列分析显示，几个成纤维细胞生长因子信号通路丰富。这里提到的结果与食用西式饮食的肥胖人群进展性NAFLD的比率增加相似。
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. 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. 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. 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. 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.
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美国肝细胞癌的流行病学：我们在哪里？我们去哪里？
影响因子：
13.5
作者：
El-Serag, Hashem B.;Kanwal, Fasiha
通讯作者：
Kanwal, Fasiha
DOI：
10.1158/1078-0432.ccr-10-2847
发表时间：
2011-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Allen E;Walters IB;Hanahan D
通讯作者：
Hanahan D
影响因子：
8.1
作者：
Fisher FM;Kim M;Doridot L;Cunniff JC;Parker TS;Levine DM;Hellerstein MK;Hudgins LC;Maratos-Flier E;Herman MA
通讯作者：
Herman MA
影响因子：
13.5
作者：
Bedossa, P;Poynard, T
通讯作者：
Poynard, T
DOI：
10.1056/nejmoa0804525
发表时间：
2008-11-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hoshida Y;Villanueva A;Kobayashi M;Peix J;Chiang DY;Camargo A;Gupta S;Moore J;Wrobel MJ;Lerner J;Reich M;Chan JA;Glickman JN;Ikeda K;Hashimoto M;Watanabe G;Daidone MG;Roayaie S;Schwartz M;Thung S;Salvesen HB;Gabriel S;Mazzaferro V;Bruix J;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR