The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity
The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity
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DOI：
10.1074/jbc.m506519200
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发表时间：
2006-01-13
影响因子：
4.8
通讯作者：
Kersten, S
中科院分区：
文献类型：
--
作者：
Mandard, S;Zandbergen, F;Kersten, S
脂肪组织分泌的蛋白质在调节葡萄糖代谢中发挥着重要作用。然而，人们对它们对脂质代谢的影响知之甚少。空腹诱导脂肪因子（FIAF/血管生成素样蛋白4/过氧化物酶体增殖体激活受体γ血管生成素相关蛋白）先前被确定为降血脂药物和胰岛素增敏噻唑烷二酮类药物的靶点。通过在外周组织中轻度过表达FIAF的转基因小鼠，我们发现FIAF是一种非常强大的脂质代谢和肥胖调节剂。FIAF过表达导致脂肪组织重量减少50%，部分原因是刺激脂肪酸氧化和脂肪解偶联。此外，FIAF过表达会增加血浆中甘油三酯、游离脂肪酸、甘油、总胆固醇和高密度脂蛋白(HDL)-胆固醇的水平。功能测试表明，FIAF过表达严重损害血浆甘油三酯清除率，但对极低密度脂蛋白的产生没有影响。高脂肪饮食放大了FIAF过表达的影响，导致高脂肪饮食喂养的FIAF转基因小鼠血浆和肝脏甘油三酯、血浆游离脂肪酸和血浆甘油水平显著升高，葡萄糖耐量受损。值得注意的是，在小鼠中，全长形式的FIAF与HDL物理相关，而截断形式的FIAF与低密度脂蛋白相关。在人类中，全长FIAF和截断FIAF都与HDL相关。综合数据表明，通过与血浆脂蛋白的物理关联，FIAF作为来自脂肪和其他组织的强大信号，防止脂肪储存并刺激脂肪动员。我们的数据表明，FIAF信号的紊乱可能与血脂异常有关。
Proteins secreted from adipose tissue are increasingly recognized to play an important role in the regulation of glucose metabolism. However, muchless is known about their effect on lipid metabolism. The fasting-induced adipose factor (FIAF/angiopoietin-like protein 4/peroxisome proliferator-activated receptor gamma angiopoietin-related protein) was previously identified as a target of hypolipidemic fibrate drugs and insulin-sensitizing thiazolidinediones. Using transgenic mice that mildly overexpress FIAF in peripheral tissues we show that FIAF is an extremely powerful regulator of lipid metabolism and adiposity. FIAF overexpression caused a 50% reduction in adipose tissue weight, partly by stimulating fatty acid oxidation and uncoupling in fat. In addition, FIAF overexpression increased plasma levels of triglycerides, free fatty acids, glycerol, total cholesterol, and high density lipoprotein (HDL)-cholesterol. Functional tests indicated that FIAF overexpression severely impaired plasma triglyceride clearance but had no effect on very low density lipoprotein production. The effects of FIAF overexpression were amplified by a high fat diet, resulting in markedly elevated plasma and liver triglycerides, plasma free fatty acids, and plasma glycerol levels, and impaired glucose tolerance in FIAF transgenic mice fed a high fat diet. Remarkably, in mice the full-length form of FIAF was physically associated with HDL, whereas truncated FIAF was associated with low density lipoprotein. In human both full-length and truncated FIAF were associated with HDL. The composite data suggest that via physical association with plasma lipoproteins, FIAF acts as a powerful signal from fat and other tissues to prevent fat storage and stimulate fat mobilization. Our data indicate that disturbances in FIAF signaling might be involved in dyslipidemia.