A polymorphism in the gene encoding procolipase produces a colipase, Arg92Cys, with decreased function against long-chain triglycerides
A polymorphism in the gene encoding procolipase produces a colipase, Arg92Cys, with decreased function against long-chain triglycerides
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DOI：
10.1194/jlr.m700371-jlr200
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发表时间：
2007-11-01
影响因子：
6.5
通讯作者：
Lowe, Mark E.
中科院分区：
文献类型：
--
作者：
D'Silva, Sheryl;Xiao, Xunjun;Lowe, Mark E.
2型糖尿病是一种多因素和多基因疾病，患病率不断增加。最近，在两个人群中，编码前脂肪酶的基因多态性（92位精氨酸被半胱氨酸取代）与2型糖尿病相关。由于前脂肪酶在膳食脂肪代谢中起着关键作用，影响前脂肪酶功能的多态性可能会影响2型糖尿病的发展。我们假设Arg92Cys多态性具有功能性后果。为了验证我们的假设，我们在酵母表达系统中表达重组半胱氨酸92（Cys92）前脂肪酶，并比较纯化的Cys92与更常见的精氨酸92（Arg92）前脂肪酶的功能和稳定性。Cys92完全恢复了胆盐抑制脂肪酶与短链和中链甘油三酯的活性，但只有50%的Arg92功能与长链甘油三酯。在4摄氏度下储存后，Cys92失去了用中链和长链甘油三酯恢复胰甘油三酯脂肪酶活性的能力。功能丧失与Cys92不能将脂肪酶锚在乳剂表面上和半胱氨酸氧化有关。储存后，Cys92中未发生可检测的降解或分子内二硫键形成。我们的研究结果表明，Arg92Cys多态性降低Cys92辅脂酶的功能。这种变化可能会导致2型糖尿病的发展。
Type 2 diabetes mellitus is a multifactorial and polygenic disorder with increasing prevalence. Recently, a polymorphism in the gene encoding procolipase, a cysteine for arginine substitution at position 92, was associated with type 2 diabetes in two human populations. Because procolipase plays a critical role in dietary fat metabolism, polymorphisms that affect the function of procolipase could influence the development of type 2 diabetes. We hypothesized that the Arg92Cys polymorphism has functional consequences. To test our hypothesis, we expressed recombinant cysteine 92 ( Cys92) procolipase in a yeast expression system and compared the function and stability of purified Cys92 with that of the more common arginine 92 ( Arg92) procolipase. Cys92 fully restored the activity of bile-salt inhibited lipase with short- and medium-chain triglycerides but only had 50% of Arg92 function with long-chain triglycerides. After storage at 4 degrees C, Cys92 lost the ability to restore pancreatic triglyceride lipase activity with medium- and long-chain triglycerides. The loss of function correlated with the inability of Cys92 to anchor lipase on an emulsion surface and oxidation of the cysteine. No detectable degradation or intramolecular disulfide formation occurred in Cys92 after storage. Our findings demonstrate that the Arg92Cys polymorphism decreases the function of Cys92 colipase. This change may contribute to the development of type 2 diabetes.