R. K. Montgomery

Lactose intolerance and the genetic regulation of intestinal lactase-phlorizin hydrolase.

Lactase‐phlorizin hydrolase, which hydrolyzes lactose, the major carbohydrate in milk, plays a critical role in the nutrition of the mammalian neonate. Lactose intolerance in adult humans is common, usually due to low levels of small intestinal lactase. Low lactase levels result from either intestinal injury or (in the majority of the worlds adult population) alterations in the genetic expression of lactase. Although the mechanism of decreased lactase levels has been the subject of intensive investigation, no consensus has yet emerged. Recent studies have begun to define the cellular and molecular biology of this enzyme. In animals and humans, a glycosylated precursor is proteolytically cleaved to yield the mature enzyme on the microvillus membrane of the enterocyte, bound to the lipid bilayer only by a hydrophobic anchor sequence. The enzyme hydrolyzes lactose, phlorizin, and glycosylceramides. A decline in lactase specific activity occurs at the time of weaning in most mammalian species; in most humans who have low lactase activity as adults, the decline occurs at approximately 3‐5 years of age. In a few human groups, the elevated juvenile level of lactase specific activity persists throughout adulthood. These developmental patterns of lactase expression are most likely regulated at the level of gene transcription.—Montgomery, R. K.; Büller, H. A.; Rings, E. H. H. M.; Grand, R. J. Lactose intolerance and the genetic regulation of intestinal lactase‐phlorizin hydrolase. FASEB J. 5: 2824‐2832; 1991.

Changing genes; losing lactase

Transcriptional regulation of the lactase-phlorizin hydrolase ( LPH ) gene by polymorphisms is associated with persistence of high levels of intestinal lactase activity or non-persistence Lactase-phlorizin hydrolase ( LPH ), an intestinal microvillus membrane enzyme that hydrolyses lactose, is a critical enzyme for neonatal nutrition. The developmental pattern of lactase expression in the human fetus is distinct from that of similar digestive enzymes. Before week 24 of gestation, intestinal lactase activity is low. It then begins to increase, and during the third trimester lactase activity increases markedly until levels in term neonates are at or above those of infants aged 2–11 months.1 Lactase exhibits a characteristic proximal to distal pattern of expression in the small intestine; enzyme activity is greatest in the mid- jejunum, with decreasing activity both proximally and distally, resulting in minimal activity in the proximal duodenum and the terminal ileum.2 In most human populations, lactase activity decreases during mid-childhood (about five years of age), resulting in low levels from that age onwards. This pattern is similar to that seen in all other mammals examined, with a reduction in intestinal lactase activity at weaning to a fraction of that found in the suckling newborn. In striking contrast, a minority of the human population, especially people of Northern European extraction and a few other racial groups, retain high levels of activity throughout adult life.3 Persistence of elevated lactase activity is thought to be a relatively recent human evolutionary development, arising within the last 10 000 years, coincident with the development of dairying.4 A small number of subjects with lactase non-persistence have been demonstrated to have an abnormality in the intracellular processing of newly synthesised LPH protein, indicating post-transcriptional control of non-persistence.5 However, it is now clear that in humans, as in all mammals studied, the primary mechanism of …

Clinical Aspects of Lactose Intolerance in Children and Adults

The principal carbohydrate of human milk is the disaccharide lactose. In human and all mammalian species, lactose is hydrolyzed in the small intestine by lactase-phlorizin hydrolase, also abbreviated as lactase. The absence of lactase results in the passage of undigested lactose into the large intestine and is associated with a well-known clinical syndrome: lactose intolerance. Low lactase levels result either from intestinal injury or, as in the majority of worlds adult population, from alterations in the genetic expression of lactase. In this review terminology, pathophysiology, symptoms, diagnostic procedures, and therapy of lactose intolerance will be discussed.

Characterisation of humoral trophic factors involved in intestinal adaptation using a 3T3 cell growth factor assay.

Indirect evidence has suggested that circulating trophic factor(s) are involved in intestinal adaptation. A 3T3 fibroblast cell culture system was used to more directly delineate the presence of such factors. Rats were divided into four groups; C-unop, those undergoing no surgery, S, those in which a dorsal slit was made; C-op, those in which the peritoneum was incised; and R, those undergoing 80% intestinal resection. At the time of death at 24 hours, one week and two weeks postoperative, stimulation of DNA synthesis in the 3T3 cells was noted after incubation with platelet free plasma from the C-op and R groups, and simultaneously an increase in ileal DNA specific activity occurred. Characterisation of the plasma fraction with growth factor activity revealed it to have a MW of greater than 6,000 and less than 14,000 d. The factor(s) was resistant to reduction with DTT, and was partially inactivated by heating to 60 degrees C. The use of 3T3 cell growth factor assay system allows further characterisation of circulating factors involved in intestinal adaptation.