Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle
Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle
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DOI：
10.1074/jbc.m108640200
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发表时间：
2002-04-12
影响因子：
4.8
通讯作者：
Zechner, R
中科院分区：
文献类型：
--
作者：
Haemmerle, G;Zimmermann, R;Zechner, R
激素敏感脂肪酶(HSL)被认为在各种组织中从甘油三酯(TG)、二甘油三酯和胆固醇酯中动员脂肪酸方面发挥着重要作用。由于HSL介导的脂肪组织(AT)中甘油三酯(TG)的脂解直接将非酯化脂肪酸(NEFA)输送到血管系统，该酶有望影响许多代谢过程，包括血浆脂和脂蛋白的代谢。在目前的研究中，我们在缺乏HSL表达的诱导突变小鼠品系(HSL-Ko小鼠)中检测了这些代谢变化。在禁食期间，当AT强烈诱导HSL时，HSL-KO动物的血浆NEFA(-40%)和TG(-63%)浓度显著降低，而总胆固醇和高密度脂蛋白(HDLc)水平升高(+34%)。除了高密度脂蛋白胆固醇浓度的增加，这些差异在喂食的动物中没有观察到，在喂食的动物中，HSL活性通常很低。空腹HSL-KO小鼠血浆甘油三酯水平下降的主要原因是由于NEFA从外周到肝脏的转运减少，导致肝脏极低密度脂蛋白(VLDL)合成减少。肝脏TG储备量的减少(-99%)和血浆中酮体浓度的显著降低(-80%)也表明NEFA转运减少。空腹HSL-KO小鼠血浆NEFA和TG水平的降低与VLDL-TG分解率的增加和心肌、骨骼肌和白色AT中组织特异性脂蛋白脂酶(LPL)活性的诱导有关。棕色AT时，LPL活性降低。心肌VLDL分解率的增加和LPL活性的增加都不能为心脏提供足够的NEFA，从而导致心肌组织TG水平的下降。我们的结果表明，HSL缺乏通过协调下调肌肉和白色脂肪组织中VLDL合成和上调LPL来显著影响富含TG的脂蛋白的代谢。这些变化导致了一种“抗动脉粥样硬化”的脂蛋白图谱。
Hormone-sensitive lipase (HSL) is believed to play an important role in the mobilization of fatty acids from triglycerides (TG), diglycerides, and cholesteryl esters in various tissues. Because HSL-mediated lipolysis of TG in adipose tissue (AT) directly feeds non-esterified fatty acids (NEFA) into the vascular system, the enzyme is expected to affect many metabolic processes including the metabolism of plasma lipids and lipoproteins. In the present study we examined these metabolic changes in induced mutant mouse lines that lack HSL expression (HSL-ko mice). During fasting, when HSL is normally strongly induced in AT, HSL-ko animals exhibited markedly decreased plasma concentrations of NEFA (-40%) and TG (-63%), whereas total cholesterol and HDL cholesterol levels were increased (+34%). Except for the increased HDL cholesterol concentrations, these differences were not observed in fed animals, in which HSL activity is generally low. Decreased plasma TG levels in fasted HSL-ko mice were mainly caused by decreased hepatic very low density lipid lipoprotein (VLDL) synthesis as a result of decreased NEFA transport from the periphery to the liver. Reduced NEFA transport was also indicated by a depletion of hepatic TG stores (-99%) and strongly decreased ketone body concentrations in plasma (-80%). Decreased plasma NEFA and TG levels in fasted HSL-ko mice were associated with increased fractional catabolic rates of VLDL-TG and an induction of the tissue-specific lipoprotein lipase (LPL) activity in cardiac muscle, skeletal muscle, and white AT. In brown AT, LPL activity was decreased. Both increased VLDL fractional catabolic rates and increased LPL activity in muscle were unable to provide the heart with sufficient NEFA, which led to decreased tissue TG levels in cardiac muscle. Our results demonstrate that HSL deficiency markedly affects the metabolism of TG-rich lipoproteins by the coordinate down-regulation of VLDL synthesis and up-regulation of LPL in muscle and white adipose tissue. These changes result in an "anti-atherogenic" lipoprotein profile.