Lacourse K A, Friis-Hansen L, Rehfeld J F, Samuelson L C
Department of Physiology, University of Michigan, Ann Arbor 48109-0622, USA.
FEBS Lett. 1997 Oct 13;416(1):45-50. doi: 10.1016/s0014-5793(97)01164-2.
The fat mouse strain exhibits a late-onset obesity syndrome associated with a mutation in the gene encoding carboxypeptidase E (CPE). Since CPE plays a central role in the biosynthesis of a number of regulatory peptides, including gastrin, we examined the biogenesis and processing of progastrin in fat/fat mice by measuring gastrin mRNA, carboxyamidated gastrin and its processing intermediates in the stomach. The tissue concentration of carboxyamidated (i.e. bioactive) gastrin was only slightly reduced (601 +/- 28 pmol/g in fat/fat mice vs. 715 +/- 43 pmol/g in wild-type controls). However, progastrin processing intermediates accumulated excessively with an 86-fold increase in the concentration of the CPE substrate, glycyl-arginine extended gastrin, and a seven-fold increase in the concentration of glycine-extended gastrin. Accordingly, the total progastrin product was doubled, as was the concentration of gastrin mRNA. Plasma concentrations of carboxyamidated gastrin were, however slightly reduced both in fasted fat/fat mice and postprandially. The results show that the CPE mutation diminishes the efficiency of progastrin processing, but gastrin synthesis is nevertheless increased to maintain an almost normal production of bioactive gastrins. By comparison with other neuroendocrine prohormones, progastrin processing in CPE-deficient mice is unique. Hence, the increase of glycine-extended gastrin in combination with normal levels of carboxyamidated gastrin suggests that G-cells may have another biosynthetic pathway for gastrin.
肥胖小鼠品系表现出一种迟发性肥胖综合征，与编码羧肽酶E（CPE）的基因突变有关。由于CPE在包括胃泌素在内的多种调节肽的生物合成中起核心作用，我们通过测量胃中胃泌素mRNA、酰胺化胃泌素及其加工中间体，研究了肥胖/肥胖小鼠中胃泌素原的生物合成和加工过程。酰胺化（即生物活性）胃泌素的组织浓度仅略有降低（肥胖/肥胖小鼠中为601±28 pmol/g，野生型对照中为715±43 pmol/g）。然而，胃泌素原加工中间体过度积累，CPE底物甘氨酰-精氨酸延伸胃泌素的浓度增加了86倍，甘氨酸延伸胃泌素的浓度增加了7倍。相应地，胃泌素原产物总量增加了一倍，胃泌素mRNA的浓度也增加了一倍。然而，无论是禁食的肥胖/肥胖小鼠还是餐后，酰胺化胃泌素的血浆浓度都略有降低。结果表明，CPE突变降低了胃泌素原加工的效率，但胃泌素合成仍增加，以维持生物活性胃泌素的几乎正常产生。与其他神经内分泌前体激素相比，CPE缺陷小鼠中胃泌素原的加工是独特的。因此，甘氨酸延伸胃泌素的增加与酰胺化胃泌素的正常水平相结合，表明G细胞可能有另一条胃泌素生物合成途径。
