Zsigmond E, Fuke Y, Li L, Kobayashi K, Chan L
Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA.
J Lipid Res. 1998 Sep;39(9):1852-61.
The interaction of lipoprotein lipase (LPL) with triglyceride-rich lipoproteins is governed by a number of factors, such as apolipoprotein (apo) C-II. The role of apoE in lipolysis is controversial. We made the unexpected observation that apoE-deficient mice were resistant to heparin-induced lipolysis; this study aims at examining the underlying mechanism for this observation. Compared to wild-type mice, apoE-deficient mice had significantly higher very low density lipoprotein (VLDL) and chylomicron remnant (VLDL/CMR) concentrations and moderately lower lipase activity (15.5 +/- 1.3 mU/ml vs. 22.9 +/- 2.5 mU/ml). Unlike in wild-type mice where the injection of heparin reduced total plasma triglycerides by 50% and VLDL/CMR triglycerides by over 95%, the injection of heparin into apoE-deficient mice did not significantly affect plasma lipids. Similarly, in vitro, purified human LPL (hLPL) almost completely hydrolyzed VLDL/CMR isolated from wild-type mice, but had no effect on VLDL/CMR from apoE-deficient mice. However, when the amount of apoE-deficient VLDL/CMR was reduced to an equivalent level as in wild-type mice, LPL hydrolyzed 94% of VLDL/CMR triglycerides. In order to increase the ratio of LPL to VLDL/CMR in vivo, we injected an adenovirus containing the human LPL cDNA into apoE-deficient mice, which produced marked liver-specific overexpression of LPL and significant reduction of VLDL/CMR (93%) and total plasma triglyceride concentrations (87%). Thus, apoE is not required for LPL activity in vivo or in vitro. Under certain pathological conditions, such as severe hyperlipidemia, the LPL pathway may be saturated and efficient lipolysis can proceed only if the ratio of substrate particles to LPL is adjusted to a more normal range.
脂蛋白脂肪酶（LPL）与富含甘油三酯的脂蛋白之间的相互作用受多种因素调控，如载脂蛋白（apo）C-II。载脂蛋白E（apoE）在脂解过程中的作用存在争议。我们意外地观察到，载脂蛋白E缺陷小鼠对肝素诱导的脂解具有抗性；本研究旨在探究这一观察结果背后的潜在机制。与野生型小鼠相比，载脂蛋白E缺陷小鼠的极低密度脂蛋白（VLDL）和乳糜微粒残粒（VLDL/CMR）浓度显著更高，而脂肪酶活性则适度降低（分别为15.5±1.3 mU/ml和22.9±2.5 mU/ml）。与野生型小鼠不同，在野生型小鼠中注射肝素可使血浆总甘油三酯降低50%，VLDL/CMR甘油三酯降低超过95%，而向载脂蛋白E缺陷小鼠注射肝素对血浆脂质并无显著影响。同样，在体外，纯化的人LPL（hLPL）几乎能完全水解从野生型小鼠分离出的VLDL/CMR，但对载脂蛋白E缺陷小鼠的VLDL/CMR却没有作用。然而，当将载脂蛋白E缺陷的VLDL/CMR量降至与野生型小鼠相当的水平时，LPL可水解94%的VLDL/CMR甘油三酯。为了在体内提高LPL与VLDL/CMR的比例，我们将携带人LPL cDNA的腺病毒注射到载脂蛋白E缺陷小鼠体内，这导致肝脏特异性显著过表达LPL，并使VLDL/CMR（93%）和血浆总甘油三酯浓度（87%）显著降低。因此，无论在体内还是体外，LPL活性均不需要apoE。在某些病理条件下，如严重高脂血症，LPL途径可能会饱和，只有将底物颗粒与LPL的比例调整到更正常的范围，高效脂解才能进行。
