Levak-Frank S, Hofmann W, Weinstock P H, Radner H, Sattler W, Breslow J L, Zechner R
Spezialforschungsbereich Biomembrane Research Center, Karl-Franzens University, A-8010 Graz, Austria.
Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3165-70. doi: 10.1073/pnas.96.6.3165.
The tissue-specific expression of lipoprotein lipase (LPL) in adipose tissue (AT), skeletal muscle (SM), and cardiac muscle (CM) is rate-limiting for the uptake of triglyceride (TG)-derived free fatty acids and decisive in the regulation of energy balance and lipoprotein metabolism. To investigate the tissue-specific metabolic effects of LPL, three independent transgenic mouse lines were established that expressed a human LPL (hLPL) minigene predominantly in CM. Through cross-breeding with heterozygous LPL knockout mice, animals were generated that produced hLPL mRNA and enzyme activity in CM but lacked the enzyme in SM and AT because of the absence of the endogenous mouse LPL gene (L0-hLPL). LPL activity in CM and postheparin plasma of L0-hLPL mice was reduced by 34% and 60%, respectively, compared with control mice. This reduced LPL expression was sufficient to rescue LPL knockout mice from neonatal death. L0-hLPL animals developed normally with regard to body weight and body-mass composition. Plasma TG levels in L0-hLPL animals were increased up to 10-fold during the suckling period but normalized after weaning and decreased in adult animals. L0-hLPL mice had normal plasma high-density lipoprotein (HDL)-cholesterol levels, indicating that LPL expression in CM alone was sufficient to allow for normal HDL production. The absence of LPL in SM and AT did not cause detectable morphological or histopathological changes in these tissues. However, the lipid composition in AT and SM exhibited a marked decrease in polyunsaturated fatty acids. From this genetic model of LPL deficiency in SM and AT, it can be concluded that CM-specific LPL expression is a major determinant in the regulation of plasma TG and HDL-cholesterol levels.
脂蛋白脂肪酶（LPL）在脂肪组织（AT）、骨骼肌（SM）和心肌（CM）中的组织特异性表达是甘油三酯（TG）衍生的游离脂肪酸摄取的限速因素，并且在能量平衡和脂蛋白代谢的调节中起决定性作用。为了研究LPL的组织特异性代谢作用，建立了三个独立的转基因小鼠品系，它们主要在CM中表达人LPL（hLPL）小基因。通过与杂合LPL基因敲除小鼠杂交，产生了在CM中产生hLPL mRNA和酶活性，但由于缺乏内源性小鼠LPL基因而在SM和AT中缺乏该酶的动物（L0-hLPL）。与对照小鼠相比，L0-hLPL小鼠CM和肝素后血浆中的LPL活性分别降低了34%和60%。这种LPL表达的降低足以使LPL基因敲除小鼠免于新生儿死亡。L0-hLPL动物在体重和身体组成方面发育正常。L0-hLPL动物在哺乳期血浆TG水平增加高达10倍，但断奶后恢复正常，成年动物中降低。L0-hLPL小鼠的血浆高密度脂蛋白（HDL）胆固醇水平正常，表明仅CM中的LPL表达就足以实现正常的HDL产生。SM和AT中缺乏LPL并未导致这些组织中可检测到的形态学或组织病理学变化。然而，AT和SM中的脂质组成显示多不饱和脂肪酸显著减少。从SM和AT中LPL缺乏的这种遗传模型可以得出结论，CM特异性LPL表达是血浆TG和HDL胆固醇水平调节的主要决定因素。
