Catalytically inactive lipoprotein lipase expression in muscle of transgenic mice increases very low density lipoprotein uptake:: Direct evidence that lipoprotein lipase bridging occurs in vivo
Catalytically inactive lipoprotein lipase expression in muscle of transgenic mice increases very low density lipoprotein uptake:: Direct evidence that lipoprotein lipase bridging occurs in vivo
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DOI：
10.1073/pnas.95.23.13841
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发表时间：
1998-11-10
影响因子：
11.1
通讯作者：
Breslow, JL
中科院分区：
文献类型：
--
作者：
Merkel, M;Kako, Y;Breslow, JL
脂蛋白脂酶（LPL）是血浆甘油三酯水解的中心酶。体外研究表明，LPL还可以通过不依赖于催化活性但需要LPL作为脂蛋白和蛋白聚糖或受体之间的分子桥梁的途径增强脂蛋白摄取到细胞中，为了研究这种桥梁功能是否发生在who中，建立了两个转基因小鼠系，表达在催化三联体（Asp（156））中突变的肌肉肌酸激酶启动子驱动的人LPL（hLPL）小基因，Asn），突变的hLPL仅在肌肉中表达，并在肝素后血浆中产生3，100和3，500 ng/ml的同源二聚体hLPL蛋白，但没有hLPL催化活性。在肝素前血浆中发现小于5 ng/ml的hLPL，表明突变的LPL的蛋白聚糖结合没有受损。失活LPL的表达不能挽救LPL敲除小鼠的新生儿死亡。在野生型（LPL 2）背景下，无活性LPL降低极低密度脂蛋白（VLDL）-甘油三酯。在杂合子LPL敲除背景（LPL 1）背景下，两个转基因系中的血浆甘油三酯水平降低22%和33%。注射放射性标记的VLDL后，观察到胆固醇衍生脂肪酸（LPL 2，1.7 x; LPL 1，1.8 x）、核心胆固醇醚（LPL 2，2.3 x; LPL 1，2.7 x）和载脂蛋白（LPL 1，1.8 x;显著低于胆固醇醚）的肌肉摄取增加。来自转基因系的骨骼肌具有与在肌肉中表达活性hLPL的小鼠相似的糖原积累的血管病变。总之，似乎无活性LPL可以在体内起作用以介导VLDL从血浆中去除并摄取到其表达的组织中。
Lipoprotein lipase (LPL) is the central enzyme in plasma triglyceride hydrolysis. In vitro studies have shown that LPL also can enhance lipoprotein uptake into cells via pathways that are independent of catalytic activity but require LPL as a molecular bridge between lipoproteins and proteoglycans or receptors, To investigate whether this bridging function occurs in who, two transgenic mouse lines were established expressing a muscle creatine kinase promoter-driven human LPL (hLPL) minigene mutated in the catalytic triad (Asp(156) to Asn), Mutated hLPL was expressed only in muscle and led to 3,100 and 3,500 ng/ml homodimeric hLPL protein in post-heparin plasma but no hLPL catalytic activity. Less than 5 ng/ml hLPL was found in preheparin plasma, indicating that proteoglycan binding of mutated LPL was not impaired. Expression of inactive LPL did not rescue LPL knock-out mice from neonatal death. On the wild-type (LPL2;) background, inactive LPL decreased very low density lipoprotein (VLDL)-triglycerides. On the heterozygote LPL knockout background (LPL1) background, plasma triglyceride levels were lowered 22 and 33% in the two transgenic lines. After injection of radiolabeled VLDL, increased muscle uptake was observed for triglyceride-derive fatty acids (LPL2, 1.7x; LPL1, 1.8 x), core cholesteryl ether (LPL2, 2.3 x; LPL1, 2.7 x), and apolipoprotein (LPL1, 1.8x; significantly less than cholesteryl ether). Skeletal muscle from transgenic lines had a mitochondriopathy with glycogen accumulation similar to mice expressing active hLPL in muscle, In conclusion, it appears that inactive LPL can act in vivo to mediate VLDL removal from plasma and uptake into tissues in which it is expressed.