Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets
Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets
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DOI：
10.1074/jbc.m113.495366
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发表时间：
2013-11-22
影响因子：
4.8
通讯作者：
Olivecrona, Gunilla
中科院分区：
文献类型：
--
作者：
Larsson, Mikael;Vorrsjo, Evelina;Olivecrona, Gunilla
已知载脂蛋白 (apo) C-I 和 C-III 可抑制脂蛋白脂肪酶 (LPL) 活性，但其分子机制仍不清楚。我们提出的证据表明，apoC-I 或 apoC-III 在与富含甘油三酯的脂蛋白结合时，会阻止 LPL 与脂质/水界面的结合。这导致酶的脂肪分解活性降低。定点诱变揭示，位于 apoC-III 分子中心的疏水性氨基酸残基对于附着到脂肪乳颗粒并因此抑制 LPL 活性至关重要。富含甘油三酯的脂蛋白可稳定 LPL 并保护该酶免受血管生成素样蛋白 4 (angptl4) 等失活因子的影响。在富含甘油三酯的颗粒中添加 apoC-I 或 apoC-III 会严重削弱它们对 LPL 的保护作用，并使该酶更容易被 angptl4 失活。这些观察结果是使用乳糜微粒以及合成脂肪乳剂 Intralipid 观察到的。在 LPL 激活蛋白 apoC-II 存在的情况下，需要更多的 apoC-I 或 apoC-III 来从脂质/水界面置换 LPL。总之，我们表明 apoC-I 和 apoC-III 通过取代脂肪乳液颗粒中的 LPL 来抑制脂肪分解。我们还提出了这些载脂蛋白在 angptl4 等因素导致的 LPL 不可逆失活中的作用。
Apolipoproteins (apo) C-I and C-III are known to inhibit lipoprotein lipase (LPL) activity, but the molecular mechanisms for this remain obscure. We present evidence that either apoC-I or apoC-III, when bound to triglyceride-rich lipoproteins, prevent binding of LPL to the lipid/water interface. This results in decreased lipolytic activity of the enzyme. Site-directed mutagenesis revealed that hydrophobic amino acid residues centrally located in the apoC-III molecule are critical for attachment to lipid emulsion particles and consequently inhibition of LPL activity. Triglyceride-rich lipoproteins stabilize LPL and protect the enzyme from inactivating factors such as angiopoietin-like protein 4 (angptl4). The addition of either apoC-I or apoC-III to triglyceride-rich particles severely diminished their protective effect on LPL and rendered the enzyme more susceptible to inactivation by angptl4. These observations were seen using chylomicrons as well as the synthetic lipid emulsion Intralipid. In the presence of the LPL activator protein apoC-II, more of apoC-I or apoC-III was needed for displacement of LPL from the lipid/water interface. In conclusion, we show that apoC-I and apoC-III inhibit lipolysis by displacing LPL from lipid emulsion particles. We also propose a role for these apolipoproteins in the irreversible inactivation of LPL by factors such as angptl4.