Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Arterioscler Thromb Vasc Biol. 2012 May;32(5):1204-10. doi: 10.1161/ATVBAHA.112.245696. Epub 2012 Feb 16.
Lipoprotein lipase (LPL) is a principal enzyme in lipoprotein metabolism, tissue lipid utilization, and energy metabolism. LPL is synthesized by parenchymal cells in adipose, heart, and muscle tissues followed by secretion to extracellular sites, where lipolyic function is exerted. The catalytic activity of LPL is attained during posttranslational maturation, which involves glycosylation, folding, and subunit assembly within the endoplasmic reticulum. A lipase-chaperone, lipase maturation factor 1 (Lmf1), has recently emerged as a critical factor in this process. Previous studies demonstrated that loss-of-function mutations of Lmf1 result in diminished lipase activity and severe hypertriglyceridemia in mice and human subjects. The objective of this study is to investigate whether, beyond its role as a required factor in lipase maturation, variation in Lmf1 expression is sufficient to modulate LPL activity in vivo.
To assess the effects of Lmf1 overexpression in adipose and muscle tissues, we generated aP2-Lmf1 and Mck-Lmf1 transgenic mice. Characterization of relevant tissues revealed increased LPL activity in both mouse strains. In the omental and subcutaneous adipose depots, Lmf1 overexpression was associated with increased LPL specific activity without changes in LPL mass. In contrast, increased LPL activity was due to elevated LPL protein level in heart and gonadal adipose tissue. To extend these studies to humans, we detected association between LMF1 gene variants and postheparin LPL activity in a dyslipidemic cohort.
Our results suggest that variation in Lmf1 expression is a posttranslational determinant of LPL activity.
脂蛋白脂肪酶（LPL）是脂蛋白代谢、组织脂质利用和能量代谢的主要酶。LPL 由脂肪、心脏和肌肉组织的实质细胞合成，然后分泌到细胞外部位，在那里发挥脂肪分解作用。LPL 的催化活性在翻译后成熟过程中获得，该过程涉及在内质网中进行糖基化、折叠和亚基组装。最近，一种脂肪酶伴侣，脂肪酶成熟因子 1（Lmf1），已成为该过程中的关键因素。先前的研究表明，Lmf1 的功能丧失突变导致小鼠和人类受试者的脂肪酶活性降低和严重的高甘油三酯血症。本研究的目的是研究 Lmf1 表达的变异是否足以在体内调节 LPL 活性，超出其作为脂肪酶成熟必需因素的作用。
为了评估 Lmf1 在脂肪和肌肉组织中过表达的影响，我们生成了 aP2-Lmf1 和 Mck-Lmf1 转基因小鼠。对相关组织的特征描述显示，两种小鼠品系的 LPL 活性均增加。在网膜和皮下脂肪组织中，Lmf1 过表达与 LPL 特异性活性增加相关，而 LPL 质量没有变化。相比之下，心脏和性腺脂肪组织中 LPL 活性的增加是由于 LPL 蛋白水平升高所致。为了将这些研究扩展到人类，我们在血脂异常队列中检测到 LMF1 基因变异与肝素后 LPL 活性之间的关联。
我们的结果表明，Lmf1 表达的变异是 LPL 活性的翻译后决定因素。
