肌肉衍生的血管生成素样蛋白4由脂肪酸通过过氧化物酶体增殖物激活受体（PPAR）-δ诱导产生，并且在人类中具有代谢相关性。
Muscle-derived angiopoietin-like protein 4 is induced by fatty acids via peroxisome proliferator-activated receptor (PPAR)-delta and is of metabolic relevance in humans.
作者信息
Staiger Harald, Haas Carina, Machann Jürgen, Werner Roman, Weisser Melanie, Schick Fritz, Machicao Fausto, Stefan Norbert, Fritsche Andreas, Häring Hans-Ulrich
机构信息
Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Eberhard-Karls-University Tübingen, Tübingen, Germany.
出版信息
Diabetes. 2009 Mar;58(3):579-89. doi: 10.2337/db07-1438. Epub 2008 Dec 15.
OBJECTIVE
Long-chain fatty acids (LCFAs) contribute to metabolic homeostasis in part via gene regulation. This study's objective was to identify novel LCFA target genes in human skeletal muscle cells (myotubes).
RESEARCH DESIGN AND METHODS
In vitro methods included culture and treatment of human myotubes and C2C12 cells, gene array analysis, real-time RT-PCR, Western blotting, ELISA, chromatin immunoprecipitation, and RNA interference. Human subjects (two cohorts) were characterized by oral glucose tolerance test, hyperinsulinemic-euglycemic clamp, magnetic resonance imaging and spectroscopy, and standard blood analyses (glucose, insulin, C-peptide, and plasma lipids).
RESULTS
We show here that ANGPTL4 (encoding angiopoietin-like protein 4) represents a prominent LCFA-responsive gene in human myotubes. LCFA activated peroxisome proliferator-activated receptor (PPAR)-delta, but not PPAR-alpha or -gamma, and pharmacological activation of PPAR-delta markedly induced ANGPTL4 production and secretion. In C2C12 myocytes, knockdown of PPARD, but not of PPARG, blocked LCFA-mediated ANGPTL4 induction, and LCFA treatment resulted in PPAR-delta recruitment to the ANGPTL4 gene. In addition, pharmacological PPAR-delta activation induced LIPE (encoding hormone-sensitive lipase), and this response crucially depended on ANGPTL4, as revealed by ANGPTL4 knockdown. In a human cohort of 108 thoroughly phenotyped subjects, plasma ANGPTL4 positively correlated with fasting nonesterified fatty acids (P = 0.0036) and adipose tissue lipolysis (P = 0.0012). Moreover, in 38 myotube donors, plasma ANGPTL4 levels and adipose tissue lipolysis in vivo were reflected by basal myotube ANGPTL4 expression in vitro (P = 0.02, both).
CONCLUSIONS
ANGPTL4 is produced by human myotubes in response to LCFA via PPAR-delta, and muscle-derived ANGPTL4 seems to be of systemic relevance in humans.
目的
长链脂肪酸（LCFAs）部分通过基因调控作用于代谢稳态。本研究的目的是在人骨骼肌细胞（肌管）中鉴定新的LCFA靶基因。
研究设计与方法
体外方法包括人肌管和C2C12细胞的培养与处理、基因芯片分析、实时逆转录聚合酶链反应、蛋白质免疫印迹法、酶联免疫吸附测定、染色质免疫沉淀和RNA干扰。通过口服葡萄糖耐量试验、高胰岛素正常血糖钳夹试验、磁共振成像和波谱分析以及标准血液分析（葡萄糖、胰岛素、C肽和血浆脂质）对人类受试者（两个队列）进行特征分析。
结果
我们在此表明，ANGPTL4（编码血管生成素样蛋白4）是人类肌管中一个显著的LCFA反应基因。LCFA激活过氧化物酶体增殖物激活受体（PPAR）-δ，但不激活PPAR-α或-γ，PPAR-δ的药理学激活显著诱导ANGPTL4的产生和分泌。在C2C12肌细胞中，敲低PPARD而非PPARG可阻断LCFA介导的ANGPTL4诱导，LCFA处理导致PPAR-δ募集至ANGPTL4基因。此外，PPAR-δ的药理学激活诱导LIPE（编码激素敏感性脂肪酶），如ANGPTL4敲低所示，这种反应关键依赖于ANGPTL4。在一个由108名经过全面表型分析的受试者组成的人类队列中，血浆ANGPTL4与空腹非酯化脂肪酸呈正相关（P = 0.0036），与脂肪组织脂解呈正相关（P = 0.001）。此外，在38名肌管供体中，体外基础肌管ANGPTL4表达反映了体内血浆ANGPTL4水平和脂肪组织脂解（两者P = 0.02）。
结论
人肌管通过PPAR-δ对LCFA作出反应产生ANGPTL4，且肌肉来源的ANGPTL4在人类中似乎具有全身相关性。
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