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Published on: October 4, 2017
The Arg92Cys colipase polymorphism impairs function and secretion by increasing protein misfolding
Xunjun Xiao1, Michael R Ferguson, Kelsey E Magee
1Department of Pediatrics, Childrenrsquos Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Journal of Lipid Research
|December 4, 2012
Summary
A common colipase gene variant (Arg92Cys) leads to misfolded protein, impairing fat digestion. This suggests a potential link between altered colipase function and type-2 diabetes risk.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Colipase is crucial for efficient dietary fat digestion.
- A specific colipase polymorphism (Arg92Cys) is linked to increased type-2 diabetes risk, but the mechanism is unclear.
Purpose of the Study:
- To investigate if the Arg92Cys polymorphism causes colipase misfolding, affecting its intracellular transport and function.
- To determine the impact of Cys92 colipase on pancreatic triglyceride lipase (PTL) activity and fat digestion.
Main Methods:
- Expressed wild-type (Arg92) and variant (Cys92) colipase in HEK293T cells.
- Analyzed colipase secretion, intracellular retention, and protein folding using gel electrophoresis.
- Assessed the functional activity of secreted colipase in stimulating PTL with various triglyceride substrates.
Main Results:
- Cys92 colipase exhibited reduced secretion and increased intracellular aggregation in an insoluble form compared to Arg92 colipase.
- Secreted Cys92 colipase showed diminished ability to stimulate PTL, particularly with long-chain triglycerides, and had longer lag times for substrate interaction.
- Misfolded Cys92 colipase did not induce unfolded protein response (UPR) or endoplasmic reticulum (ER) stress.
Conclusions:
- The Arg92Cys colipase variant leads to misfolded protein, reduced secretion, and impaired fat digestion.
- This suggests that decreased functional colipase and inefficient fat digestion may contribute to the increased type-2 diabetes risk associated with this polymorphism.
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