Fatty acid binding protein-4 promotes alcohol-dependent hepatosteatosis and hepatocellular carcinoma progression.
Fatty acid binding protein-4 promotes alcohol-dependent hepatosteatosis and hepatocellular carcinoma progression.
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DOI：
10.1016/j.tranon.2020.100975
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发表时间：
2021-01
影响因子：
5
通讯作者：
McKillop IH
中科院分区：
文献类型：
--
作者：
Attal N;Sullivan MT;Girardi CA;Thompson KJ;McKillop IH
脂肪肝(肝骨病)是ALD和NAFLD的标志。FABP4通常在脂肪细胞和巨噬细胞中表达。ALD导致脂肪变性肝细胞合成/释放FABP4。FABP4刺激肝癌细胞生长和迁移。脂肪肝(肝骨病)是酒精依赖和肥胖患者常见的早期病理。脂肪酸结合蛋白-4(FABP4)在脂肪细胞和巨噬细胞中正常表达，是细胞内脂质运动/储存的调节因子。本研究旨在探讨FABP4在酒精性肝病(ALD)和肝细胞癌(HCC)中的表达和功能。采用慢性乙醇喂养的小鼠模型和患者标本，分析FABP4的表达。将人肝癌细胞和转导了CYP2E1的肝癌细胞暴露于乙醇中，分析FABP4的表达，或暴露于rhFABP4(在没有或存在ERK、p38-MAPK或JNK1/2抑制剂的情况下)，并检测细胞的增殖和迁移。肝成骨病-ALD小鼠模型显示肝脏FABP4的mRNA和蛋白水平升高，并证实FABP4在肝细胞中表达。在肝癌细胞中，依赖于细胞色素P450 2的乙醇代谢在体外诱导FABP4的表达，外源性的重组人FABP4刺激细胞的增殖和迁移，这种作用被ERK和JNK1/2抑制而被取消。在ALD/ALD-肝细胞癌患者中也检测到FABP4升高，但在病毒性肝炎/肝细胞癌患者中未检测到。总之，这些数据表明乙醇代谢诱导了肝脏FABP4的表达，FABP4促进了肝癌细胞的增殖/迁移。这些数据表明，肝源性FABP4可能是ALD潜在背景下肝脏病灶扩大和/或肝癌进展过程中的一个重要的旁分泌内分泌因子。
Fatty liver disease (hepatosteatosis) is a hallmark of ALD and NAFLD. FABP4 is normally expressed in adipocytes and macrophages. ALD leads to FABP4 synthesis/release from steatotic hepatocytes. FABP4 stimulates hepatoma cell growth and migration. Fatty liver disease (hepatosteatosis) is a common early pathology in alcohol-dependent and obese patients. Fatty acid binding protein-4 (FABP4) is normally expressed in adipocytes and macrophages and functions as a regulator of intracellular lipid movement/storage. This study sought to investigate hepatic FABP4 expression and function in alcoholic liver disease (ALD) and hepatocellular carcinoma (HCC). Using chronic ethanol fed mouse models and patient samples FABP4 expression was analyzed. Human HCC cells, and HCC cells transfected to express CYP2E1, were exposed to ethanol and analyzed for FABP4 expression, or exposed to rhFABP4 (in the absence/presence of ERK, p38-MAPK or JNK1/2 inhibitors) and cell proliferation and migration measured. Hepatosteatotic-ALD mouse models exhibited increased hepatic FABP4 mRNA and protein levels, with FABP4 expression confirmed in hepatocytes. In HCC cells, CYP2E1-dependent ethanol metabolism induced FABP4 expression in vitro and exogenous rhFABP4 stimulated proliferation and migration, effects abrogated by ERK and JNK1/2 inhibition. Increased FABP4 was also detected in ALD/ALD-HCC patients, but not patients with viral hepatitis/HCC. Collectively these data demonstrate ethanol metabolism induces hepatic FABP4 expression and FABP4 promotes hepatoma cell proliferation/migration. These data suggest liver-derived FABP4 may be an important paracrine-endocrine factor during hepatic foci expansion and/or hepatoma progression in the underlying setting of ALD.
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影响因子：
29.4
作者：
El-Serag HB
通讯作者：
El-Serag HB
影响因子：
82.9
作者：
通讯作者：
--
FABP4 通过 MAPK 依赖性途径诱导血管平滑肌细胞增殖和迁移。
影响因子：
3.7
作者：
Girona J;Rosales R;Plana N;Saavedra P;Masana L;Vallvé JC
通讯作者：
Vallvé JC
影响因子：
4.8
作者：
Harjes, Ulrike;Bridges, Esther;Harris, Adrian L.
通讯作者：
Harris, Adrian L.
影响因子：
8
作者：
Laouirem, Samira;Sannier, Aurelie;Paradis, Valerie
通讯作者：
Paradis, Valerie