Georgitis, John W.; Galant, Stanley; Lloyd, Mark; Kundu, Sudeep; Fish, James E.; Banerji, Donald; Hamedani, Parvez Author Information

Despite extensive study in both humans and nonhuman mammals the mechanisms which regulate intestinal lactase activity, particularly during development, are incompletely understood. Our previous studies of human adults are consistent with an important role of lactase-phlorizin hydrolase (LPH) mRNA abundance in determining the lactase persistence/nonpersistence phenotypes. Our intent in the present study was to determine the role of LPH mRNA in the regulation of lactase in children. We therefore studied duodenal mucosal biopsies from 39 children undergoing diagnostic upper endoscopy in whom significant small intestinal and nutritional disease was excluded. We found no relationship between the level of LPH mRNA and lactase enzymatic activity. Our observations suggest the importance of posttranscriptional mechanisms in lactase regulation in human children.

Relative deficiency of intestinal lactase activity during adulthood, adult hypolactasia, is a common condition worldwide. We studied the regulation of lactase-phlorizin hydrolase in normal and adult hypolactasic subjects by correlating transcript abundance in intestinal biopsies with relative synthetic rates for the protein in cultured intestinal explants. After metabolic labelling studies in six subjects, precursor lactase-phlorizin hydrolase was identified in amounts directly proportional to the enzyme-specific activity suggesting that levels of intestinal lactase are regulated by synthetic rate. Total intestinal RNA was extracted from biopsies of these subjects and three hypolactasic adults who had participated in previous biosynthesis studies. Transcript levels were markedly reduced in deficient subjects who demonstrated diminished lactase-phlorizin hydrolase synthesis. The sequence of 1 kb of 5'-flanking region of the lactase-phlorizin hydrolase gene was determined in two hypolactasic subjects and two controls. No sequence variability was identified to account for differences in mRNA levels or biosynthetic rates between the two groups.A single hypolactasic subject previously characterized as demonstrating delayed posttranslational processing, showed message levels intermediate between other deficients and controls. These results suggest that in the majority of our subjects, pretranslational mechanisms account for the predominate regulatory control of lactase-phlorizin hydrolase expression in the proximal intestine.