Substrate-Induced Regulation of Gene Expression in the Pancreas

Based on the hypothesis of Pavlov [1] and early experiments with rats [2, 3], it was thought that diets rich in either fats, proteins or carbohydrates would cause a selective increase of synthesis of those pancreatic enzymes corresponding to the predominant substrates. Although correct when diets contained at least 15 percent protein, this concept had to be revised, because in extreme situations, such as a zero protein/high carbohydrate diet, the relevant enzymes (i.e., serine proteases and amylase) appeared to be inversely correlated to the amount of substrate fed [4]. The accumulated output of (pro)enzymes is the result of several distinct phases: first mRNA levels depend on the rate of transcription and the rate of mRNA degradation. Second, protein levels depend on the amount of available mRNA, the rate of translation, the potential size of the storage pool (zymogen granule size and density) and the rate of secretion. Individual phases have been analyzed with various tools, depending on availability of adequate technology. The focus of attention has been to correlate synthetic rates and actual tissue content of (pro)enzymes. Histochemical studies have allowed estimation of zymogen granule density. However, the molecular mechanisms by which the expression of pancreatic genes is regulated have so far not been elucidated in detail.