J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M700371-JLR200 on August 22, 2007

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Journal of Lipid Research, Vol. 48, 2478-2484, November 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

A polymorphism in the gene encoding procolipase produces a colipase, Arg92Cys, with decreased function against long-chain triglycerides

Sheryl D'Silva, Xunjun Xiao and Mark E. Lowe1

Department of Pediatrics, Children's Hospital of Pittsburgh at University of Pittsburgh Medical Center, Pittsburgh, PA 15213

Published, JLR Papers in Press, August 22, 2007.

1 To whom correspondence should be addressed. e-mail: mark.lowe{at}chp.edu

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°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.

Supplementary key words lipase • type 2 diabetes • digestion • recombinant protein • mutagenesis

Abbreviations: Arg92, arginine 92; Cys92, cysteine 92; OD280, optical density at 280 nm; PTL, pancreatic triglyceride lipase


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Copyright © 2007 by the American Society for Biochemistry and Molecular Biology.