Epidermal growth factor and transforming growth factor alpha down-regulatehuman gastric lipase gene expression

Background & Aims: It was recently reported that human gastric lipase (HGL) activity is modulated by epidermal growth factor (EGF), The aims of this s tudy were to establish the cellular localization of HGL, to assess the corr elation between HGL messenger RNA (mRNA) and protein levels, and to establi sh the molecular mechanism of action of EGF and its homologue transforming growth factor alpha (TGF-alpha) on HGL expression. Methods: Cellular locali zation of HGL was determined by immunohistochemistry using a polyclonal ant ibody. 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. Results: HGL was localized in the sec retory granules of gastric chief cells as early as 13 weeks. A close parall elism was found between the variations of mRNA, protein, and enzymic activi ty. EGF and/or TGF-alpha down-regulated HGL mRNA levels and decreased enzym ic activity. The role of the mitogen-activated protein kinase cascade in th e regulation of HGL expression was highlighted by the use of MAP kinase kin ase-1/2 inhibitor PD98059, which blunted both the activation of p42/p44(map k) and the down-regulation of HGL mRNA induced by EGF and/or TGF-alpha. Con clusions: The expression of HGL is regulated at the mRNA level, and the dow n-regulatory action of EGF and/or TGF-alpha on HGL involves the stimulation of p42/p44(mapk) cascade.