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PubMed1969

Human small-intestinal beta-galactosidases. Separation and characterization of one lactase and one hetero beta-galactosidase.

1. Two beta-galactosidases from human small-intestinal mucosa were separated by gel-filtration chromatography and the properties of the two enzymes were studied. Lactose and four hetero beta-galactosides were used as substrates. 2. One of the enzymes was particle-bound and could be partially solubilized with papain. Of the substrates hydrolysed by this enzyme, lactose was hydrolysed most rapidly. This enzyme is thus essentially a disaccharidase and is named lactase. It is presumably identical with the ;lactase 1' described earlier. 3. The other enzyme was mainly soluble and hydrolysed all artificial substrates used, whereas no lactase activity could be detected. This enzyme has therefore been designated hetero beta-galactosidase. 4. p-Chloromercuribenzoate (0.1mm) inhibited the hetero beta-galactosidase completely but did not influence the activity of the lactase. Tris was a competitive inhibitor of both enzymes. 5. The residual lactase activity in the mucosa of lactose-intolerant patients may be exerted by a small amount of remaining lactase as such, or possibly by a third enzyme with a more acid pH optimum.

Chloromercuribenzoates↗
PubMed1975

Prospective comparison of indirect methods for detecting lactase deficiency.

To compare sensitivity, specificity and convenience, four indirect methods of detecting lactase deficiency were tested prospectively in 25 subjects with biopsy-proved lactase deficiency and in 25 with normal lactase activity. After ingestion of 50 g of lactose, containing 1-14Clactose, breath hydrogen was abnormally elevated in all 25 lactase-deficient subjects (greater than 0.30 ml per minute at two hours); breath 14CO2 was below the normal range in 23, and in 19 the plasma glucose increased by less than 20 mg per deciliter. When lactose and ethanol were given together, the rise in plasma galactose remained less than 5 mg per deciliter in 24 of the lactase-deficient subjects. The specificity of the four tests was excellent, with only one false-positive plasma glucose test. Measurement of breath hydrogen is sensitive and specific, and does not require ethanol or isotopes. It is noninvasive, and is not influenced by gastric emptying or metabolic factors. We believe it to be the most suitable test for population screening for lactase deficiency.

Adult↗
PubMed1985

Dietary regulation of intestinal lactase and sucrase in adult rats: quantitative comparison of effect of lactose and sucrose.

To characterize the mechanisms leading to dietary evoked increases of lactase and sucrase activities by carbohydrates, we performed a quantitative comparison of the effects of lactose and sucrose on the corresponding disaccharidases in the jejunum of 2-month-old rats. For 7-10 days the rats were fed a low-starch (5 cal%), high-fat (73 cal%) diet, and for various periods of time (3-72 h) were given an isocaloric sucrose or lactose (20, 40, or 70 cal%) diet. Lactase and sucrase activities in jejunal homogenates were significantly increased within 3 h after the initial feeding of the sucrose (40 cal%) diet. After 3 h of feeding the sucrose diet, sucrase activity gradually increased and reached its maximum at 24 h, whereas lactase activity did not exhibit further change. Increased intake of sucrose led to an increase of lactase and sucrase activity. Within a range of doses of digestible amounts of lactose, the effect of diet containing lactose on these disaccharidase activities was similar to the effect of the diet containing sucrose. This similarity suggests the important role of the common constituent sugar, i.e., glucose. Further, analyses of response to these disaccharides along the villus-crypt axis revealed that the increase of lactase activity occurs at a more apical and broader locus of cohort of epithelial cells along the height of the villus than that of sucrase, suggesting that different mechanisms are involved in dietary regulation of lactase and sucrase.

Animals↗
PubMed1980

Immunoelectrophoretic studies on human small intestinal brush border proteins--amount of lactase protein in adult-type hypolactasia.

Jejunal biopsies from 15 Greenlandic and three Danish patients with adult type hypolactasia and nine Greenlandic and 15 Danish patients with normal lactase activity were analysed quantitatively for lactase protein by crossed immunoelectrophoresis. A constant correlation between the amount of lactase activity and immunologically reactive lactase protein was demonstrated irrespective of the lactase activity level. As immunoelectrophoresis expresses the amount of enzyme protein independent of the enzymatic activity, it is concluded that the low enzymatic activity in adults with hypolactasia is caused by a low amount of lactase and not by a modified inactive enzyme.

Adult↗
PubMed1990

The biosynthetic basis of adult lactase deficiency.

The intestinal brush-border enzyme lactase splits lactose into its component monosaccharides, glucose and galactose. Relative deficiency of the enzyme during adulthood is a common condition worldwide and is frequently associated with symptoms of lactose intolerance. We studied the synthesis and processing of lactase in normal and adult hypolactasic subjects using human intestinal explants in organ culture. Metabolic labeling experiments in our control subjects with [35S]methionine followed by immunoprecipitation, sodium dodecyl sulfate-polyacrylamide-gel electrophoresis, and fluorography demonstrated that newly synthesized lactase is initially recognized as a precursor molecule with a relative molecular weight (Mr) of 205,000. Over the course of several hours most of the labeled lactase was converted to a mature form of 150,000 Mr. Transiently appearing forms of 215,000 and 190,000 Mr were identified and were felt to represent intermediary species generated during intracellular processing. We identified two distinct alterations in lactase biosynthesis accounting for adult hypolactasia. Studies in three deficient subjects demonstrated markedly reduced synthesis of the precursor protein though posttranslational processing appeared identical to normal. Multiple studies in a fourth deficient subject demonstrated synthesis of ample amounts of precursor lactase but reduced conversion to the mature active form of the enzyme.

Adult↗
PubMed1991

Increased serum osteocalcin levels in patients with lactase deficiency.

Serum levels of osteocalcin, a noncollagenous bone matrix protein, have been found to be a specific biochemical parameter of bone formation. In the literature in subjects with osteoporosis, an increased incidence of lactase deficiency has been described. We therefore determined the serum levels of osteocalcin in 10 patients with lactase deficiency and in 20 control subjects by radioimmunoassay. The patients with lactase deficiency were dietary treated and had a very low daily calcium intake. Serum osteocalcin levels were significantly higher in the patients with lactase deficiency than in the control subjects. In contrast, serum levels of parathyroid hormone, alkaline phosphatase, calcium, and phosphorus were not statistically different in the two groups. Our data suggest an increased rate of bone turnover in patients with lactase deficiency on a low calcium diet; possibly calcium supplementation is indicated in dietary-treated patients with lactase deficiency.

Adult↗
PubMed1990

[Different expression of the mRNA detected by the cDNA for fetal rat lactase in the jejunum and colon].

To study the genetical expression of lactase-phlorizin hydrolase in the jejunum and colon of developing rats we cloned the corresponding cDNA in a cDNA library constructed from the intestinal RNA of fetal rats. The structure of this 6.1 kb-long cDNA was similar to that of the cDNA of adult rabbits and humans, indicating that the enzyme was synthesized as a precursor organized into repeated homologous domains. The mRNA for lactase-phlorizin hydrolase accumulated at a constant level throughout the development in the jejunum despite the decline in lactase activity occurring at weaning. In the colon, the cDNA for lactase-phlorizin hydrolase hybridized to a transcript that was similar in size to the jejunal mRNA. This mRNA was transiently found during the first week after birth. Its rate of accumulation defined the level of lactase activity measured at this stage. We conclude that the expression of lactase-phlorizin hydrolase during the development is essentially regulated at the post-transcriptional level in the jejunum, in contrast to the colon where it is regulated at the pretranslational level.

Animals↗
PubMed1988

13CO2 breath test using naturally 13C-enriched lactose for detection of lactase deficiency in patients with gastrointestinal symptoms.

A 13CO2 breath test using naturally enriched 13C-lactose as a substrate was performed in 47 patients with chronic abdominal pain or chronic diarrhea, taken from a population with a low prevalence of primary acquired lactase deficiency. The cumulative 13CO2 excretion 4 hours after 13C-lactose intake was compared with the H2 breath excretion and with jejunal lactase activity. A physiologically significant relation was found between the cumulative 13CO2 excretion (at 4 hours) and lactase activity, 14.5% 13CO2 excretion being the best cutoff point for discrimination between patients with low and normal lactase activity. The 13CO2 breath test was found to be more sensitive (0.84 versus 0.68) and more specific (0.96 versus 0.89) than the H2 breath test in detecting low jejunal lactase activity. Concordant results of both breath tests performed simultaneously give a reliable picture of the lactose absorption status of the patient. Discordance in results of 13CO2 and H2 lactose breath tests, if not explained by history, indicates in which patients a jejunal biopsy should be performed. If lactase activity and morphology of the biopsy are normal, other causes of discordance must be investigated.

Abdomen↗
PubMed1984

Stimulation of lactase synthesis induced by starvation in the jejunum of adult rat.

The effects of actinomycin D and of cycloheximide administration have been investigated on the enzyme activities of the jejunal brush border membrane in adult rats after a 48-hour period of starvation. The modifications in the protein and enzyme patterns of the brush border membrane and the incorporation of radiolabelled amino acid in the protein band corresponding to lactase have been studied in the nourished and in the starved animal. The results show that actinomycin D administration did not modify the stimulation of lactase activity caused by starvation whereas cycloheximide completely inhibited this process. The stimulation of lactase activity, in the starved animal, is related to a quantitative increase of the corresponding protein band and with enhanced incorporation of L-[3H]valine in this protein band after separation of brush border proteins by gel electrophoresis. It is concluded that the stimulation of lactase activity observed during starvation is the consequence of de novo synthesis of lactase molecules and that this process is regulated at a translational level. A general hypothesis is proposed in order to clear up partly the mechanism involved in the stimulation of lactase activity by food deprivation in the adult rat.

Animals↗
PubMed1984

Clinical significance of enzymatic deficiencies in the gastrointestinal tract with particular reference to lactase deficiency.

The study of deficiencies of small intestinal brush-border hydrolases increased our knowledge about the specific functions of hydrolases in the digestion of smaller molecules on the microvillus surface of the absorptive cells. The sucrase-isomaltase (SI) complex has been shown to be synthesized as a precursor (pro-sucrase-isomaltase) which is then incorporated into the membrane. The hydrophobic N-terminal end of the molecule is anchored in the lipid bilayer. In SI deficiency the molecular base of the disease is still not clear. Absence of SI activity could be due to complete lack of precursor synthesis or to structural changes within the N-terminal end of the SI-complex. Deficiencies of peptide hydrolases have not been reported with the exception of enteropeptidase (EP). Here a congenital deficiency of the enzyme was observed as the primary defect in enzyme synthesis within the enterocytes and as a secondary defect due to exocrine pancreatic insufficiency. In contrast to the primary EP deficiency, the activity of EP can be restored in the cases of exocrine pancreatic insufficiency by treatment with pancreatic extracts. Primary lactase deficiency exists in various forms. Besides congenital lactase deficiency, the late onset or adult type of lactase deficiency has been observed. The latter occurs in many different ethnic groups around the world. Here, using gel electrophoresis and immunoelectrophoresis, the lack of enzyme activity could be shown to be a primary defect in enzyme protein synthesis. In man and in the rat, two different lactases have been identified. In contrast to adult lactase, fetal lactase contains sialic acid at the end of carbohydrate side chains.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1976

[Milk intolerance, lactose intolerance and lactase deficiency in partial resection of the stomach].

Of 40 patients with a partial gastrectomy (Billroth-II) 10 developed a milk intolerance and 11 had a lactase deficiency, the latter in 4 cases appearing together with a decrease in other disaccharidases. Only 2 of the 11 lactase-deficient patients complained of milk intolerance. The Ethanol lactose tolerance test (ELTT) was performed in 21 patients and was found to be abnormal in 6. Whereas cases of abnormal ELTT usually (4 of 6 cases) showed a lactase deficiency, only 2 patients with milk intolerance showed an abnormal ELTT and lactase deficiency. Milk intolerance can therefore only exceptionally be explained by lactase deficiency, and lack of lactase in the upper jejunum usually does not produce intolerance symptoms. Moreover, in comparable determinations from the afferent and efferent jejunal loop no differences in enzyme activities could be observed.

Adult↗
PubMed1998

Primary lactase deficiency and past malarial endemicity in Sardinia.

BACKGROUND: It has recently been suggested that primary lactase deficiency might have been selected for by malaria, as occurred for beta-thalassaemia and glucose 6-phosphate dehydrogenase deficiency. However, recently we have found that the prevalence of primary lactase deficiency in the area of Sassari (Northern Sardinia), where, in the past, there was intermediate malarial endemicity, is comparable to that observed in the adult population from other areas of Southern Italy where malaria was less endemic. AIMS: To address the problem further, we have determined the prevalence of primary lactase deficiency, glucose 6-phosphate dehydrogenase deficiency deficiency and beta-thalassaemia trait in the populations of three Sardinian villages which differ in altitude above sea-level, socioeconomic features, history of endemic malaria and prevalence of b-thalassaemia and glucose 6-phosphate dehydrogenase deficiency. SUBJECTS: We tested 138 adult males: 53 were from Fonni (a non-malarial mountain village, with a strong pastoral tradition), 38 from Lodé (a village with a similar pastoral tradition, but high malarial endemicity in the past) and 47 from Terralba (a lowland fishing village with an agricultural tradition and heavy malarial morbidity and mortality). METHODS: A blood sample was obtained in all subjects for determination of HbA2 and glucose 6-phosphate dehydrogenase activity. Lactase deficiency was assessed by measuring breath hydrogen production after oral administration of lactose (50 g), by gas-chromatography. RESULTS: The frequencies of glucose 6-phosphate dehydrogenase deficiency and of beta-thalassaemia trait in the non-malarial village of Fonni were strikingly low, compared to frequencies found in the two villages (Terralba and Lodé) with a very high past malarial morbidity. In contrast, there was no significant difference in the prevalence of lactase deficiency in the three groups of subjects from the three villages. CONCLUSIONS: These data obtained in Northern Sardinia do not support the hypothesis of a selection of primary lactase deficiency by malaria. For definitive conclusions, however, the malaria hypothesis should be tested in other parts of the world.

Adolescent↗
PubMed1996

Proteolytic processing of human lactase-phlorizin hydrolase is a two-step event: identification of the cleavage sites.

Human lactase-phlorizin hydrolase (EC 3.2.1.23/62) is a major disaccharidase in the microvillus membrane of small intestinal epithelial cells. The enzyme is synthesized as a single-chain precursor protein and undergoes proteolytic processing during maturation. We studied proteolytic processing of human lactase-phlorizin hydrolase in transfected COS-1, Caco-2, and MDCK cells using metabolic labeling, surface immunoprecipitation, protease sensitivity assays, and microsequencing. Furthermore, we generated mutated forms of the enzyme to alter potential proteolytic cleavage sites and expressed these in Caco-2 and COS-1 cells. Since the N-terminal amino acid of microvillus lactase-phlorizin hydrolase corresponds to Ala869 in the precursor protein, it has been speculated that processing occurs at position Arg868-Ala869. Substitution of Arg868 with isoleucine, lysine, or glutamic acid had no effect on the proteolytic processing of pro-LPH in Caco-2 cells. As in wild-type enzyme a processed 160-kDa form was generated. These data are not consistent with a primary proteolytic processing at position Arg868-Ala869. Using amino-terminal amino acid sequencing of this processed form isolated from stable transfected MDCK cells we identified the cleavage site at Arg734-Leu735. Treatment of pro-lactase-phlorizin hydrolase expressed in COS-1 and MDCK cells by trypsin yielded a 145-kDa form with an identical amino terminal as the mature microvillus enzyme isolated from intestinal mucosa (Ala869). These data provide unambiguous evidence of a two-step processing of human lactase-phlorizin hydrolase. The first cleavage occurs intracellularly after a dibasic site (Arg734-Leu735) and yields the 160-kDa intermediate form. In a second step the intermediate form inserted into the microvillus membrane is trimmed to the mature enzyme by luminal trypsin.

Animals↗
PubMed2006

Dietary sucrose enhances intestinal lactase gene expression in euthyroid rats.

It is postulated that dietary carbohydrates and thyroid hormones are major regulators for expression of the lactase/phlorizin hydrolase (LPH) gene in rat jejunum. In this study, we investigated the effects of thyroid hormones and dietary sucrose on LPH gene expression and lactase activity in starved rats. Firstly, animals at 8 wk of age were fed a low-starch diet (5.5% energy as cornstarch) or high-starch diet (71% energy as cornstarch) for 7 d (experiment 1). The mRNA level of LPH as well as lactase activity significantly decreased in rats fed the low-starch diet as compared to those fed the high-starch diet. To investigate the effects of thyroid hormone status, the animals previously fed the low-starch diet were starved for 3 d, and half of the animals were given intraperitoneal (i.p.) injections of 20 microg/ 100 g body weight triiodothyronine (T3) twice daily (experiment 2). The LPH mRNA level and lactase activity were elevated by starvation for 3 d, but they were repressed by the injection of T3 during starvation. To investigate the effects of dietary sucrose in starved rats, they were force-fed a sucrose diet for 6 h (experiment 3). The LPH gene expression and lactase activity were up-regulated by force-feeding a sucrose diet, only when the animals were kept in euthyroid status by daily T3 administrations. In contrast, the sucrase-isomaltase mRNA levels and sucrase activity were unaffected by force-feeding the sucrose diet for both T3-treated and untreated starved rats. Our work suggests that dietary sucrose is capable of enhancing lactase gene expression in starved rats when they have a sustainable thyroid hormone level.

Analysis of Variance↗
PubMed2005

Microsatellite variation and evolution of human lactase persistence.

The levels of haplotype diversity within the lineages defined by two single-nucleotide polymorphisms (SNPs) (-13910 C/T and -22018 G/A) associated with human lactase persistence were assessed with four fast-evolving microsatellite loci in 794 chromosomes from Portugal, Italy, Fulbe from Cameroon, São Tomé and Mozambique. Age estimates based on the intraallelic microsatellite variation indicate that the -13910*T allele, which is more tightly associated with lactase persistence, originated in Eurasia before the Neolithic and after the emergence of modern humans outside Africa. We detected significant departures from neutrality for the -13910*T variant in geographically and evolutionary distant populations from southern Europe (Portuguese and Italians) and Africa (Fulbe) by using a neutrality test based on the congruence between the frequency of the allele and the levels of intraallelic variability measured by the number of mutations in adjacent microsatellites. This result supports the role of selection in the evolution of lactase persistence, ruling out possible confounding effects from recombination suppression and population history. Reevaluation of the available evidence on variation of the -13910 and -22018 loci indicates that lactase persistence probably originated from different mutations in Europe and most of Africa, even if 13910*T is not the causal allele, suggesting that selective pressure could have promoted the convergent evolution of the trait. Our study shows that a limited number of microsatellite loci may provide sufficient resolution to reconstruct key aspects of the evolutionary history of lactase persistence, providing an alternative to approaches based on large numbers of SNPs.

Africa↗
PubMed1991

Mosaic pattern of lactase expression by villous enterocytes in human adult-type hypolactasia.

Immunohistological analysis of the expression of lactase protein in adults with hypolactasia has been carried out using monoclonal antibodies. Eight different antibodies that recognize at least three distinct epitopes on the lactase protein each gave the same result. Strong brush border staining was observed in all the lactase-persistent adults. No staining at all was detected in 9 of the hypolactasic subjects. In the remaining 12 individuals a mosaic pattern of expression was observed: small patches of enterocytes stained strongly, whereas the surrounding areas showed no staining at all. Sucrase-isomaltase, in contrast, showed no such mosaicism in these or in any of the other individuals. The mosaicism observed in the 12 hypolactasic individuals suggests that the differentiation of the columnar cells along the villus is not homogeneous. Furthermore, the existence of two patterns of expression of the lactase protein in the lactase-deficient individuals (i.e., absence of protein and mosaicism), if characteristic of the entire length of the intestine of the individuals tested, would suggest the existence of two phenotypes of adult-type hypolactasia in the population studied.

Antibodies, Monoclonal↗
PubMed1990

The effect of thyroid hormone on the activities of lactase in the culture of fetal rat intestine.

The effects of thyroid hormone on lactase activities were studied in vitro organ culture of fetal rat intestine. Triiodothyronine inhibited lactase activities regardless the presence of dexamethasone. Also triiodothyronine decreased lactase activities when added after dexamethasone increased lactase activities. Our results suggest that thyroid hormone may have a role in the maturational changes of lactase activities during weaning.

Animals↗
PubMed1991

Cortisone and thyroxine modulate intestinal lactase and sucrase mRNA levels and activities in the suckling rat.

Glucocorticoids and thyroxine modulate postnatal intestinal sucrase and lactase activities. Whether changes in enzyme activity are accompanied by changes in enzyme mRNA levels were determined in day 6 rats given thyroxine, cortisone, or thyroxine plus cortisone and killed 3 days later. Cortisone induced precocious expression of jejunal sucrase activity which was enhanced when cortisone plus thyroxine was administered; sucrase mRNA changed in parallel. Jejunal lactase activity was unaffected by thyroxine and was increased after cortisone, but not after thyroxine plus cortisone. Jejunal lactase mRNA levels increased equally after cortisone or after cortisone plus thyroxine. Thus, cortisone induces coordinated increases in sucrase and lactase activities and in corresponding mRNA levels. Thyroxine only enhances cortisone induced sucrase expression and antagonizes cortisone by depressing lactase activity post-translationally.

Animals↗