Regulation of intestinal lactase in adult hypolactasia.

Abstract

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. (J. Clin. Invest. 1992.

Characterisation of a human homologue of a yeast cell division cycle gene, MCM6, located adjacent to the 5′ end of the lactase gene on chromosome 2q21

“…1). In addition, a primer in the 3' exon (within the 3' UTR) used together with a primer 200 bases upstream from the previously characterised lactase promoter sequence [12,18], produced the same 2.4 kb band both in the clone DNA and in 5 different genomic DNA samples (2 lactase persistent, 2 non-persistent and a known heterozygote).…”

“…Diagrammatic representation of the lambda hchrlac7 clone showing the positions of the MCM6 exons and LCT exonl in relation to the EcoRI (E) and HindlII (H) sites, and to the plcl, 7 and 9 subclones and the PCR products covering the region. The previously published sequence [11,12,18] was obtained from more than five different individuals.…”

“…1 kb of sequence upstream of the start of transcription has been published [18]. To characterise the remainder of the clone, three EcoRI/HindIII subclones were partially sequenced, initially using vector primers and then further primers made to 'walk' along the sequence.…”

Molecular basis of lactase levels in adult humans.

“…Since the level of mRNA present is a critical factor in determining the rate of protein synthesis, these data are consistent with ours. A recent study of biopsy samples from six patients, correlating lactase enzyme activity, protein synthesis, and mRNA levels, presented in abstract form by Lloyd et al (19), also concluded that the fundamental level of regulation was transcriptional. Alterations in enzyme processing at weaning have recently been suggested as a mechanism for the decline in rat lactase activity (20).…”

The levels of lactase and of sucrase‐isomaltase along the rabbit small intestine are regulated both at the mRNA level and post‐translationally

“…LPH-mRNA has been reported to remain at high levels after the decline of lactase enzymatic activity in rabbits [3], rats [4][5][6], and man [3]. Others have instead observed a decline in LPH-mRNA, in adult sheep [6] and also in rats [7] and man [8,9]. The rate of biosynthesis of LPH in adult rats in vivo has been reported to be reduced as compared to that in baby rats [10] or not to be reduced at all [11,12].…”