FGFR4 prevents hyperlipidemia and insulin resistance but underlies high-fat diet-induced fatty liver
FGFR4 prevents hyperlipidemia and insulin resistance but underlies high-fat diet-induced fatty liver
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DOI：
10.2337/db07-0648
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发表时间：
2007-10-01
期刊：
影响因子：
7.7
通讯作者：
McKeehan, Wallace L.
中科院分区：
文献类型：
--
作者：
Huang, Xinqiang;Yang, Chaofeng;McKeehan, Wallace L.
成纤维细胞生长因子（FGF）家族信号通过短距离细胞间旁分泌通讯在很大程度上控制细胞内稳态。最近，FGF 15/19、21和23与代谢稳态的内分泌控制有关。介导这些作用的FGF受体同种型的身份和位置尚不清楚。目的是确定FGFR 4的作用，FGFR 4是一种同种型，已被提出在胆固醇稳态中介导回肠FGF 15/19至肝细胞FGFR 4轴，研究设计和方法-FGFR 4（-/-）小鼠-过表达组成型活性肝FGFR 4-和FGFR 4（-/-）的小鼠在肝脏中恢复了组成型活性肝FGFR 4的受试者接受足以导致肥胖的正常和慢性高脂肪饮食。然后表征全身和肝脏特异性代谢表型。正常饮食的FGFR 4缺陷小鼠表现出代谢综合征的特征，除了高胆固醇血症外，还包括白色脂肪组织质量增加、高脂血症、葡萄糖耐受不良和胰岛素抗性。令人惊讶的是，FGFR 4缺乏减轻了肥胖小鼠中高脂饮食诱导的脂肪肝，这也是代谢综合征的相关因素。FGFR 4的恢复，特别是在FGFR 4缺陷小鼠的肝细胞中，降低了血浆脂质水平并恢复了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。结论-FGFR 4在全身脂质中发挥重要作用和葡萄糖稳态。肝细胞中的FGFR 4活性通常用于预防全身性高脂血症，但矛盾的是，FGFR 4活性是与慢性高脂肪摄入和肥胖相关的脂肪肝疾病的基础。
OBJECTIVE-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.RESEARCH DESIGN AND METHODS-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.RESULTS-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.CONCLUSIONS-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.