Department of Pediatrics, Children's Hospital of Pittsburgh at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224, USA.
J Biol Chem. 2011 Jul 29;286(30):26353-63. doi: 10.1074/jbc.M111.249813. Epub 2011 Jun 7.
In newborn mice, PLRP2 is essential for fat digestion. In human infants, the role of PLRP2 in fat digestion is unclear, as it has poor activity against long-chain triglycerides in vitro. Also, many infants carry a genetic polymorphism resulting in a truncated protein, PLRP2 W340X, which may impact function significantly. We re-examined the properties of recombinant human PLRP2 and studied the impact of W340X mutation on its function. In the presence of bile salt micelles and colipase, human PLRP2 hydrolyzed long-chain tri-, di-, and monoglycerides. It hydrolyzed triolein at a level much lower than that of pancreatic triglyceride lipase, but close to that of carboxyl ester lipase, after a long lag phase, which could be eliminated by the addition of oleic acids. Human PLRP2 W340X was poorly secreted and largely retained inside the cell. The retention of the mutant protein triggered endoplasmic reticulum stress and unfolded protein responses. Our results show that earlier studies underestimated human PLRP2 activity against triolein by employing suboptimal assay conditions. In vivo, dietary fat emulsions contain fatty acids as a result of the action of gastric lipase. Consequently, PLRP2 can contribute to fat digestion during early infancy. Furthermore, infants with homozygous W340X alleles will not secrete functional PLRP2 and may have inefficient dietary fat digestion, particularly when breastfeeding is unavailable. Additionally, the aberrant folding of W340X mutant may cause chronic cellular stress and increase susceptibility of pancreatic exocrine cells to other metabolic stressors.
在新生小鼠中，PLRP2 对脂肪消化至关重要。在人类婴儿中，PLRP2 在脂肪消化中的作用尚不清楚，因为它在体外对长链甘油三酯的活性较差。此外，许多婴儿携带导致截短蛋白（PLRP2 W340X）的遗传多态性，这可能显著影响其功能。我们重新检查了重组人 PLRP2 的特性，并研究了 W340X 突变对其功能的影响。在胆汁盐胶束和辅脂酶存在的情况下，人 PLRP2 水解长链三酰基、二酰基和单酰基甘油。它水解三油酸甘油酯的水平远低于胰脂肪酶，但与羧基酯酶相近，经过很长的迟滞期后，可以通过添加油酸来消除。人 PLRP2 W340X 分泌不良，大部分滞留在细胞内。突变蛋白的保留引发内质网应激和未折叠蛋白反应。我们的结果表明，早期研究由于采用了不理想的测定条件，低估了人 PLRP2 对三油酸甘油酯的活性。在体内，由于胃脂肪酶的作用，膳食脂肪乳液中含有脂肪酸。因此，PLRP2 可以在婴儿早期为脂肪消化做出贡献。此外，携带纯合 W340X 等位基因的婴儿不会分泌功能性 PLRP2，可能无法有效消化膳食脂肪，特别是在无法母乳喂养的情况下。此外，W340X 突变体的异常折叠可能导致慢性细胞应激，并增加胰腺外分泌细胞对其他代谢应激源的敏感性。
