Epidermal growth factor and transforming growth factor alpha down-regulate human gastric lipase gene expression.

Abstract

It was recently reported that human gastric lipase (HGL) activity is modulated by epidermal growth factor (EGF). The aims of this study were to establish the cellular localization of HGL, to assess the correlation between HGL messenger RNA (mRNA) and protein levels, and to establish the molecular mechanism of action of EGF and its homologue transforming growth factor alpha (TGF-alpha) on HGL expression. Cellular localization of HGL was determined by immunohistochemistry using a polyclonal antibody. Enzymic determinations, Western blotting, and Northern hybridization were used to analyze expression of HGL mRNA, protein, lipase activity, and the p42/p44(mapk) activation status. HGL was localized in the secretory granules of gastric chief cells as early as 13 weeks. A close parallelism was found between the variations of mRNA, protein, and enzymic activity. EGF and/or TGF-alpha down-regulated HGL mRNA levels and decreased enzymic activity. The role of the mitogen-activated protein kinase cascade in the regulation of HGL expression was highlighted by the use of MAP kinase kinase-1/2 inhibitor PD98059, which blunted both the activation of p42/p44(mapk) and the down-regulation of HGL mRNA induced by EGF and/or TGF-alpha. The expression of HGL is regulated at the mRNA level, and the down-regulatory action of EGF and/or TGF-alpha on HGL involves the stimulation of p42/p44(mapk) cascade.