Huang Xinqiang, Yang Chaofeng, Luo Yongde, Jin Chengliu, Wang Fen, McKeehan Wallace L
Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX 77030, USA.
Diabetes. 2007 Oct;56(10):2501-10. doi: 10.2337/db07-0648. Epub 2007 Jul 30.
Fibroblast growth factor (FGF) family signaling largely controls cellular homeostasis through short-range intercell paracrine communication. Recently FGF15/19, 21, and 23 have been implicated in endocrine control of metabolic homeostasis. The identity and location of the FGF receptor isotypes that mediate these effects are unclear. The objective was to determine the role of FGFR4, an isotype that has been proposed to mediate an ileal FGF15/19 to hepatocyte FGFR4 axis in cholesterol homeostasis, in metabolic homeostasis in vivo.
FGFR4(-/-) mice-mice overexpressing constitutively active hepatic FGFR4--and FGFR4(-/-) with constitutively active hepatic FGFR4 restored in the liver were subjected to a normal and a chronic high-fat diet sufficient to result in obesity. Systemic and liver-specific metabolic phenotypes were then characterized.
FGFR4-deficient mice on a normal diet exhibited features of metabolic syndrome that include increased mass of white adipose tissue, hyperlipidemia, glucose intolerance, and insulin resistance, in addition to hypercholesterolemia. Surprisingly, the FGFR4 deficiency alleviated high-fat diet-induced fatty liver in obese mice, which is also a correlate of metabolic syndrome. Restoration of FGFR4, specifically in hepatocytes of FGFR4-deficient mice, decreased plasma lipid levels and restored the high-fat diet-induced fatty liver but failed to restore glucose tolerance and sensitivity to insulin.
FGFR4 plays essential roles in systemic lipid and glucose homeostasis. FGFR4 activity in hepatocytes that normally serves to prevent systemic hyperlipidemia paradoxically underlies the fatty liver disease associated with chronic high-fat intake and obesity.
成纤维细胞生长因子（FGF）家族信号主要通过短程细胞间旁分泌通讯来控制细胞内稳态。最近，FGF15/19、21和23被认为参与了代谢稳态的内分泌调控。介导这些效应的FGF受体亚型的身份和位置尚不清楚。本研究旨在确定FGFR4（一种已被提出在胆固醇稳态中介导回肠FGF15/19至肝细胞FGFR4轴的亚型）在体内代谢稳态中的作用。
将FGFR4基因敲除小鼠、组成型激活肝FGFR4的过表达小鼠以及肝脏中恢复组成型激活肝FGFR4的FGFR4基因敲除小鼠给予正常饮食和足以导致肥胖的慢性高脂饮食。然后对全身和肝脏特异性代谢表型进行表征。
正常饮食的FGFR4基因敲除小鼠表现出代谢综合征的特征，包括白色脂肪组织质量增加、高脂血症、葡萄糖不耐受和胰岛素抵抗，此外还有高胆固醇血症。令人惊讶的是，FGFR4缺乏减轻了肥胖小鼠中高脂饮食诱导的脂肪肝，而脂肪肝也是代谢综合征的一个相关因素。在FGFR4基因敲除小鼠的肝细胞中特异性恢复FGFR4，可降低血浆脂质水平并恢复高脂饮食诱导的脂肪肝，但未能恢复葡萄糖耐量和对胰岛素的敏感性。
FGFR4在全身脂质和葡萄糖稳态中起重要作用。正常情况下用于预防全身高脂血症的肝细胞中的FGFR4活性，却反常地成为与慢性高脂摄入和肥胖相关的脂肪肝疾病的基础。
