Levak-Frank S, Weinstock P H, Hayek T, Verdery R, Hofmann W, Ramakrishnan R, Sattler W, Breslow J L, Zechner R
Institute of Medical Biochemistry, Karl Franzens University, A-8010 Graz, Austria.
J Biol Chem. 1997 Jul 4;272(27):17182-90. doi: 10.1074/jbc.272.27.17182.
To determine the contribution of muscle lipoprotein lipase (LPL) to lipoprotein metabolism, induced mutant mice were generated that express human LPL exclusively in muscle. By cross-breeding heterozygous LPL knockout mice with transgenic mice expressing human LPL only in muscle, animals were obtained that express human LPL primarily in skeletal muscle on either the null (L0-MCK) or normal (L2-MCK) LPL backgrounds, and these were compared with control littermates (L2). Fed and fasted post-heparin plasma (PHP) LPL activities were increased 1.4- and 2.3-fold, respectively, in L2-MCK mice and were normal in L0-MCK mice compared with controls. The specific enzyme activities of human LPL in mouse plasma was comparable to human LPL in human PHP. Skeletal muscle LPL activity was increased in both L2-MCK and L0-MCK mice in the fed (6.6-fold) and fasted (4.2-fold in L2-MCK; and 3.4-fold in L0-MCK) states. Adipose tissue LPL mRNA and activity were not detectable in L0-MCK mice. Growth and body mass composition were similar among all groups. In the fasted and fed state, L2-MCK mice had 31% and 53% reductions, respectively, in plasma triglycerides (TG), compatible with increased PHP LPL activity. Unexpectedly, both in the fasted and fed state the L0-MCK mice also had reduced TG (22%), despite normal PHP LPL activities. Very low density lipoprotein (VLDL) turnover studies revealed that the decreased TG were due to increased particle fractional catabolic rate in both L2-MCK and L0-MCK mice. Despite reduced TG, both L2-MCK and L0-MCK mice showed reduced high density lipoprotein (HDL) cholesterol levels (16% and 19%, respectively). HDL turnover studies indicated increased HDL cholesteryl ester fractional catabolic rate in the L2-MCK and L0-MCK compared with control mice. In summary, these studies suggest that muscle LPL is particularly potent with regard to VLDL metabolism and is sufficient to compensate for the lack of LPL in other tissues with regard to lipolyzing VLDL particles. With regard to HDL, muscle LPL expression does not result in normal levels due to enhanced breakdown either by mediating accelerated HDL clearance or by failing to establish normal HDL particles that are then cleared more quickly than normal. These studies provide new insights on the tissue-specific effects of LPL on lipoprotein metabolism.
为了确定肌肉脂蛋白脂肪酶（LPL）在脂蛋白代谢中的作用，我们构建了仅在肌肉中表达人LPL的诱导型突变小鼠。通过将杂合LPL基因敲除小鼠与仅在肌肉中表达人LPL的转基因小鼠杂交，获得了在无效（L0-MCK）或正常（L2-MCK）LPL背景下主要在骨骼肌中表达人LPL的动物，并将它们与对照同窝小鼠（L2）进行比较。与对照组相比，L2-MCK小鼠喂食后和禁食后肝素后血浆（PHP）LPL活性分别增加了1.4倍和2.3倍，而L0-MCK小鼠的活性正常。小鼠血浆中人LPL的比酶活性与人类PHP中的人LPL相当。在喂食状态（6.6倍）和禁食状态（L2-MCK中为4.2倍；L0-MCK中为3.4倍）下，L2-MCK和L0-MCK小鼠的骨骼肌LPL活性均增加。在L0-MCK小鼠中未检测到脂肪组织LPL mRNA和活性。所有组的生长和身体质量组成相似。在禁食和喂食状态下，L2-MCK小鼠的血浆甘油三酯（TG）分别降低了31%和53%，这与PHP LPL活性增加一致。出乎意料的是，尽管PHP LPL活性正常，但在禁食和喂食状态下，L0-MCK小鼠的TG也降低了（22%）。极低密度脂蛋白（VLDL）周转研究表明，L2-MCK和L0-MCK小鼠中TG的降低是由于颗粒分数分解代谢率增加。尽管TG降低，但L2-MCK和L0-MCK小鼠的高密度脂蛋白（HDL）胆固醇水平均降低（分别为16%和19%）。HDL周转研究表明，与对照小鼠相比，L2-MCK和L0-MCK小鼠的HDL胆固醇酯分数分解代谢率增加。总之，这些研究表明，肌肉LPL在VLDL代谢方面特别有效，并且在分解VLDL颗粒方面足以补偿其他组织中LPL的缺乏。关于HDL，由于通过介导加速HDL清除或未能建立正常的HDL颗粒（随后比正常情况更快地清除）而导致分解增强，肌肉LPL表达并未导致正常水平。这些研究为LPL对脂蛋白代谢的组织特异性作用提供了新的见解。
