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. Lowe

Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213

Corresponding Author: mark.lowe{at}chp.edu

Type 2 diabetes mellitus is a multi-factorial 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 Cys92 procolipase in a yeast expression system and compared the function and stability of purified Cys92 to that of the more common 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 oC, Cys92 lost the ability to restore PTL 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 intra-molecular 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.

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