Indian Journal of Biochemistry & Biophysics
Vol. 43, October 2006, pp. 267-274
Minireview
Hypolactasia as a molecular basis of lactose intolerance
Kamaljit Kaur, Safrun Mahmood§ and Akhtar Mahmood*
Department of Biochemistry, Panjab University, Chandigarh 160 014
§Department
of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research,
Chandigarh 160 012, India
Received 23 May 2006; revised 21 July 2006
Lactase-phlorizin hydrolase (LPH), a membrane-bound glycoprotein present in the luminal surface of enterocytes in the
intestine is responsible for lactose intolerance, a phenomenon prevalent in humans worldwide. In the rodent intestine, the
post-natal development of the LPH follows a specific pattern, such that the enzyme levels are high in the peri-natal period,
but declines considerably upon maturation. The observed maturational decline in the LPH activity is very similar to adulttype hypolactasia observed in humans. Majority of the studies have been carried out using animal models or cell lines and a
number of hypotheses have been put forward to explain the maturational decline of lactase activity such as: (a) decreased
amount of lactase protein, (b) defect in post-translational modification of precursor lactase to the mature enzyme, and (c)
synthesis of an inactive, high molecular weight lactase with altered glycosylation, however, the precise underlying
mechanism of adult-type hypolactasia remains undefined. The present review describes the recent developments in
understanding the regulation of lactase expression and the possible mechanism of adult-type hypolactasia, as a cause of
lactose intolerance.
Keywords: Lactase-phlorizin hydrolase, Lactase activity, Adult-type hypolactasia, Lactase glycosylation and regulation,
Lactose intolerance, Lactose gene expression
Introduction
Lactose, the major carbohydrate of milk is a
disaccharide consisting of glucose and galactose
linked through β-1,4-glycosidic linkage. It is
synthesized in the mammary glands, during late
pregnancy and lactation. Lactase-phlorizin hydrolase
(LPH), a bifunctional enzyme having lactase (βgalactosidase; EC 3.2.1.23) and glucosidase (EC
3.2.1.62) activities1 is present in the brush border
membrane of small intestinal enterocytes2. Lactase
hydrolyzes lactose, whereas glucosidase is involved in
the breakdown of substances such as phlorizin,
flavonoid glucosides3 and pyridoxine-5′-β-Dglucoside4. LPH is the only enzyme that cleaves
lactose into glucose and galactose and is essential for
the survival of mammals early in the life. Post-natal
development of LPH follows a specific pattern, such
______________
*Corresponding author
Email: [email protected]
Fax: 91-0172-2541409; Tel: 91-0172-2534136
Abbreviations: BBM, brush border membrane; CLD, congenital
lactase deficiency; EGF, epidermal growth factor; HNF,
hepatocyte nuclear factor LCT, lactase gene; LBHT, lactose
breath hydrogen test; LDC, lactose digestion capacity; LPH,
lactase-phlorizin hydrolase; SNP, single nucleotide polymorphism.
that the enzyme activity is quite high at birth, but
decreases considerably upon weaning in most of the
mammalian species, including the majority of human
population, who are described as lactase nonpersistent5,6. The deficiency of lactase activity leads to
milk intolerance, a phenomenon prevalent in humans
worldwide and is associated with symptoms such as
abdominal pain, flatulence, nausea and diarrhoea7.
Lactose malabsorption
Lactose malabsorption is a normal physiological
pattern8. It occurs as a result of the inability of some
persons to digest significant amounts of lactose,
because of inadequate amounts of lactase activity.
Deficiency of lactase causes accumulation of
undigested lactose in small bowel, leading to
increased influx of fluids inside the intestinal lumen.
The unabsorbed lactose is passed into the large
intestine, which in addition to increasing fluid volume
of gastro-intestinal content, is acted upon by the
colonic bacteria, resulting in the production of shortchain fatty acids and hydrogen gas. The gas produced
can cause abdominal pain, cramps, nausea and
diarrhoea. In patients with common adult-type
hypolactasia, the amount of ingested lactose required
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INDIAN J. BIOCHEM. BIOPHYS., VOL. 43, OCTOBER 2006
Fig. 1—Factors involved in lactose intolerance [Ref: Villako K & Maaroos H (1994) Scand J Gastroenterol 29 (suppl), 36-54]
to produce symptoms varies, but is reported to be 1218 g lactose or 8-12 oz of milk9. The severity of
lactose malabsorption and the extent of symptoms are
not only a function of lactase levels in the small
intestine, but also of several other factors such as: (a)
consumption of large quantities of lactose, exceeding
the lactose digestion capacity (LDC), (b) rate of
gastric emptying time, (c) intestinal transit time, (d)
colonic microflora, and (e) age of subject10 (Fig. 1).
Biosynthesis of lactase
Lactase is encoded by a single lactase gene (LCT)
of approx. 50 kb11, located on chromosome 2q.21 in
humans12. The gene has 17 exons12 (Fig. 2) and
encodes an mRNA transcript of 6274 nucleotides
(Genbank X07994). However, in case of rodents,
lactase gene (Lct) has a location on chromosome
13q12.
Lactase protein consists of 1927 amino acids in
humans, 1926 in rabbits and 1928 in rats13-15. It is a
single polypeptide composed of a putative signal
peptide of 19 amino acids, a large pro-portion of 849
amino acids and a mature protein that contains two
catalytic sites and at the C-terminal end, a membrane
spanning domain and short cytoplasmic domain
(Fig. 3). Between the signal sequence and the
membrane anchor, four homologous regions (I to IV)
have been recognized16. Only regions III (lactase) and
IV (phlorizin hydrolase), the membrane spanning
segment and the cytosolic C-terminus makes the
“mature” LPH, which can be isolated from the brush
border membrane.
Initially, lactase is produced as a 200-220 kDa
precursor (prolactase) containing high mannose Nglycosylation. The prolactase is synthesized and
folded into a 3-D configuration within rough
endoplasmic reticulum (RER) and subsequently
transported to Golgi apparatus, where N-linked
glycans are converted into complex forms.
Commonly, this complex N-glycosylated prolactase
Fig. 2—Schematic diagram of lactase gene
Fig. 3—Human prolactase-phlorizin hydrolase insertion into
microvillus membrane
becomes O-glycosylated to some extent, leading to an
increase in molecular mass from 225-240 kDa of
prolactase. During or shortly after the transport of the
prolactase to the microvillus membrane, the precursor
is proteolytically cleaved into its mature form of 130160 kDa in humans and 120-130 kDa in rats17.
Proteolytic processing of lactase by trypsin occurs
after its passage through the Golgi apparatus, but
before insertion into the plasma membrane18 (Fig. 4).
A prodomain, comprising the N-terminally, located
734 amino acids of pro-LPH (LPHα) is found to be an
intramolecular chaperone that is critically essential in
facilitating the folding of the intermediate form
LPHβ initial19.
Developmental pattern of intestinal lactase activity
During
post-natal
development,
intestinal
maturation is associated with morphological changes,
proliferation and differentiation of cells and digestive
KAUR et al.: LACTOSE INTOLERANCE
Fig. 4—Schematic representation of lactase-phlorizin hydrolase
biosynthesis
adaptation to nutritional changes such as decrease in
lactase activity and a rise in sucrase, maltase and
aminopeptidase activities. Lactase is present
predominantly along the brush border membrane of
differentiated enterocytes and exhibits a wellcharacterized
development
pattern
in
all
mammals5,6,20-23. This restricted expression makes it
an
ideal
marker
for
fully
differentiated
enterocytes24,25.
mRNA encoding LPH in the mature human
intestinal epithelium has a complex expression along
the crypt-villus axis26. The expression of mRNA and
protein is very low in crypt cells. At crypt-villus
junction high levels of LPH mRNA appear, which are
maintained at similar levels in villus tip cells26.
Another interesting observation is that like lactase
protein, mRNA encoding lactase is not uniformly
distributed in mature enterocytes6,26,27 and is
concentrated in the cytoplasm, located below the
apical membrane. Thus, there seems to be colocalization between the lactase mRNA and lactase
protein in the apical part of the enterocytes. Recently,
we demonstrated that in vitro translation of lactase is
impaired in adult rat intestine, which suggested that
translational efficiency of mRNA to lactase is greatly
curtailed during post-natal development28. However,
the mechanism and expression of the restricted
localization of the lactase mRNA are not known.
Lactase activity exhibits a characteristic proximal
to distal gradient of expression along the length of
small intestine. In adult rat and rabbit, it is highest in
the middle jejunum and decreases both proximally
and distally, resulting in minimal activity in proximal
duodenum and terminal ileum5,21,29,30. The lactase
expression around birth differs between rodents and
humans. In rats, the lactase activity is detectable on
269
18th day of gestation and is maximal during 1st week
after birth and then begins to decline, reaching the
adult values by the end of 4th post-natal week31.
However, in humans, the lactase expression is highest
at the time of birth, probably reflecting a difference in
the intestinal maturation between rodents and humans.
In contrast to humans, the rodent intestine is not fully
mature at birth, as fully developed crypts are not
detected until 2-3 days after birth32. Lactase
expression after weaning is patchy in the distal part of
the small intestine in rabbits33. The same phenomenon
has been found in persons with adult-type
hypolactasia, both at the protein and mRNA levels34
as well as in distal parts of the small intestine in
weaned rats35. These findings imply that the low
lactase activity observed after weaning is not a
consequence of general down-regulation of lactase
expression in all enterocytes, but a complete turn-off
of lactase expression in majority of the
enterocytes34,35.
Etiology
Lactose malabsorption is prevalent worldwide and
occurs due to primary lactase deficiency or adult type
hypolactasia, secondary lactase deficiency or acquired
hypolactasia, and congenital lactase deficiency (CLD)
or alactasia. Adult-type hypolactasia is the most
common form of lactose malabsorption, which occurs
due to deficiency of lactase. Acquired hypolactasia is
present in a variety of gastro-intestinal diseases with
histological evidence of mucosal damage and
increased transit time in the jejunal mucosa36. CLD is
very rare and occurs as a result of complete loss of
lactase activity37. It manifests itself as severe
diarrhoea during breast-feeding in first few days of
life, which leads to poor weight gain, as long as
lactose-containing milk is given to the patient. It is
more common in the isolated Finnish population and
the underlying gene defect has been assigned to
chromosome 2, having location 2q21-2238.
Different methods have been used for determining
the lactase deficiency. Although, an intestinal biopsy
is the only direct method for determining lactase
activity, it cannot be regarded as a standard method,
because mucosal lactase activity varies along the
length of small intestine39,40. The genetic test of C/T
(-13910) polymorphism could be used as first-stage
screening test for adult-type hypolactasia in children.
In this case, intestinal biopsies after assaying lactase
activity could be genotyped for the C/T (-13910)
variant using PCR mini-sequencing41.
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Measuring blood glucose concentration, after an
oral dose of 50 g lactose is the most commonly used
method for testing tolerance to lactose42; rise in blood
glucose levels less than 20 mg/dL (1.1 mmol/L) is
considered as an indication of lactose maldigestion.
However, because of inter-individual variations in
gastric emptying and glucose metabolism, this test
cannot be considered sensitive to establish lactase
deficiency. Another test involves the determination of
urinary galactose after inclusion of ethanol with the
lactose load by decreasing galactose metabolism to
glucose.
The measurement of breath hydrogen response
after oral dose of lactose is considered to be fairly
reliable test in detecting lactose maldigestion43. This
test is based on the principle that unhydrolyzed
lactose is fermented by the colonic microflora,
producing hydrogen and methane, which get diffused
into the blood circulation and excreted in expired air.
The test is positive in 90% of patients with lactose
malabsorption43,44. Recently, an automated rapid
genotyping assay for LPH C→T-13910 has been
developed and a relationship was found between
positive lactose breath hydrogen test (LBHT) and
symptoms of lactose intolerance45.
Prevalence of adult-type hypolactasia
Lactase non-persistence, also known as adult-type
hypolactasia is an autosomal recessive condition that
affects about half of the world’s population38. Its
prevalence varies considerably between different
races and populations. It is the predominant
phenotype in the native populations of Australia and
America and in the Pacific, East and Southeast Asia
and Tropical Africa46. With the exception of the
population of northern and central Europe, 70-100%
of adults worldwide are lactose malabsorbers. Lactose
tolerance or breath hydrogen tests have provided
accurate mapping of the prevalence of lactose
malabsorption worldwide. The prevalence of primary
lactose malabsorption is 3-5% in Scandinavia, 17% in
Finland, 2-15% in northern Europeans and 6-23% in
American Whites and central Europeans47. The
maximum frequency occurs in case of American
Indians (80-100%) and Asians (95-100%)10. The
frequency increases as one moves south and west. A
similar trend is seen from north to south of India48.
The prevalence of lactose malabsorption is found to
be 30% in Northern India and 70% in Southern India
respectively49,50.
Polymorphisms
associated with
adult-type
hypolactasia
Several nucleotide polymorphisms have been
described in the lactase gene (LCT) and the
surrounding regions51,52. Two single nucleotide
polymorphisms (SNPs) C/T-13910 and G/A-22018 are
found to be associated with adult-type hypolactasia52.
C-13910 at position -13910 upstream of lactase gene is
100% associated and a G-22018 at position -22018 is
more than 95% associated with lactase nonpersistence, in Finnish population. Troelsen et al53
investigated the role of these nucleotide
polymorphisms for LPH gene expression. They
reported that T-13910 variant enhances the LPH
promoter approximately 4 times more than the C-13910
variant in differentiated Caco-2 cells, showing that the
molecular difference between lactase persistence and
non-persistence is caused by mutation at position
−13910. The T-13910 and A-22018 variants are associated
with lactase persistence54. Individuals with the
persistent T-13910 allele showed 11-times higher LCT
mRNA content in their intestinal mucosa, compared
to those with the non-persistent C-13910 allele,
suggesting regulation of LCT gene at the
transcriptional level. Identification of the C/T-13910
variant has enabled haplotype analysis of the close
polymorphisms and microsatellite markers in the
genomic region54.
Lactase and intestinal glycosylation
The apical membrane of intestinal cell is exposed
to a rapidly changing environment in suckling
animals, which culminates at weaning and requires
adaptive alteration in membrane composition.
Chemical analysis of microvillus surface during
suckling period shows that membrane is rich in sialic
acid55, but has low level of fucose. Upon weaning,
sialic acid content decreases sharply, while fucose
content begins to rise to attain adult levels. After
weaning, there occurs a complete reversal of molar
ratio of fucose/sialic acid from suckling animals56.
The age-related changes from sialylation to
fucosylation of BBM-bound glycoproteins are due to
a shift in sialyl and fucosyl transferase levels in small
intestine57. During post-natal development, the active
form of lactase, before weaning is sialylated and
inactive form after weaning is fucosylated58. This shift
from sialylation to fucosylation may also be
associated with susceptibility of lactase to degradation
by luminal proteases, thus leading to hypolactasia.
Kaur et al59 have shown the decrease in lactase
KAUR et al.: LACTOSE INTOLERANCE
activity in 8-day-old pups on incubating the
membranes with luminal wash isolated from the adult
rat intestine. Some investigators have suggested that
the decrease in lactase-specific activity in adult rats is
due to the synthesis of an inactive high molecular
weight protein with altered glycosylation, rather than
active form found in young animals5. The structure of
glycan chains may also be important for the transport
of lactase and for the integration into the apical
membrane of the enterocyte60. Administration of
thyroxine to rats is reported to decrease lactase
activity and a simultaneous increase of a fucosytated
inactive form of this enzyme, which is abundant in
adult membranes, but only present in trace amounts in
suckling rat intestine61.
Regulation of lactase gene expression
The lactase gene has a complicated pattern of
regulation during post-natal development. It is
maximally expressed in apical villus cells and the
dietary sucrose elicits the enhancement of its
impression in villus cells, where respective mRNA
transcripts are accumulated in large quantities62. Its
expression is spatially restricted along the
longitudinal axis of the gut51. Although the
mechanism of regulation of the spatial and temporal
restriction of its expression is not fully understood,
however, it is widely accepted that regulation of its
expression occurs mainly at the post-transcriptional
level in the jejunum63, whereas it is controlled at the
pre-translational level in the colon64. A close
correlation exists between lactase activity and its
mRNA levels in rats5 and humans65. The lactase
activity is also reported to be regulated at the level of
gene transcription66. It has been demonstrated that a
distinct 5′-region of the lactase promoter directs the
intestine-specific expression in small intestine of
transgenic mice and the regulatory sequences are
localized to a 1.2 kb region upstream of the lactase
transcription start site67.
In vivo studies have identified the lactase promoter
and the transcription factors regulating its expression.
A lactase promoter of 150 bps, found just upstream of
the transcriptional initiation site is conserved in
rodents, rabbits and humans. The presence of these
conserved sequences indicates the localization of
regulatory cis-elements (transcription factor-binding
sites) in this region. Three cis-elements, i.e. CEIa,
CE2c and a GATA site have been identified using
deleted and mutated versions of receptor/promoter
gene constructs. The cis-elements bind to the
271
transcription factors for activating a particular gene
expression. The importance of binding of
transcription factors (Cdx-1, HNFIα and GATA-4) to
these sites has been investigated in cell cultures using
CaCo-2 cells, isolated from a primary colonic tumour
from a 72-year-old Caucasian male68. The expression
of the transcription factors plays a key role in
demonstrating the regulation of LCT gene
expression35.
Cdx-2 (caudal-related homeodomain) is an intestinespecific homeodomain-containing transcription factor
that activates the promoters of intestinal genes
through specific interactions with cis element CEIa69.
It plays an important role as a regulator of intestinal
specific expression and differentiation of the lactase
and sucrase-isomaltase promoters70-72. LPH gene
expression is repressed in the non-Cdx-2 producing
cells, because their binding sequence is different from
that of Cdx-2 binding sites73. The Cdx-2 is highly
expressed in colon and its expression decreases from
distal to proximal portion of the intestine, but its
expression is not the sole criterion for demonstrating
lactase gene expression. Other transcription factors
such as HNF-1α and GATA also play a key role in
regulating the lactase expression.
HNF1 (hepatocyte nuclear factor – 1α and 1-β)
specifically binds to CE2-site, which has been shown
to be important for lactase promoter activity74,75.
HNF-1α is expressed along the entire length of the
small intestine. It is the main activator through CE2c
site, as it activates the lactase promoter approximately
10-times more than HNF-1β. Interaction (in vivo and
in vitro) between GATA-5 and HNF-1α is required
for the synergistic activation of the human LPH
promoter. It occurs through C-terminal zinc finger
and basic regions of GATA-5 and the homeodomain
of HNF-1α76. GATA factors (-4, -5 and -6) also play a
role in binding and activating lactase promoter
genes74,76. GATA-4 is the main GATA factor that
binds the lactase promoter. GATA-4 and 5 are mainly
expressed in the differentiated intestinal epithelial
cells, whereas GATA-6 is highly expressed in the
proliferating crypt cells. GATA-4 exhibits a gradual
decline from a high expression in proximal part to low
level in distal ileum76.
The expression of HNF-1α increases after weaning,
whereas the expression of GATA-4 and Cdx-2
remained relatively unchanged during post-natal
development of rat intestine77. However, the influence
of these changes on the post-natal decline of lactase
activity remains unknown. Studies by Wang et al78
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INDIAN J. BIOCHEM. BIOPHYS., VOL. 43, OCTOBER 2006
have shown that rat lactase promoter contains a pdx-1
binding site, which is expressed in duodenum and
proximal jejunum and its expression is inversely
related with lactase expression.
Dietary and hormonal regulation of lactase
Both nutritional and hormonal factors are involved
in the decline of specific activity of lactase. The
starvation, however, induces lactase levels in rats79. A
high carbohydrate diet for 1 week, with corn starch
forming 70% of the total energy and with no added
lactose, increased disaccharidase activities (lactase,
sucrase and maltase) in the rat jejunum80. Elevated
mRNA levels for lactase have been reported in rats
fed sucrose-enriched diet, within 12 h of intake,
suggesting that dietary sucrose enhances the
transcription of lactase gene62.
Kaur et al81 reported the effect of saturated dietary
fats on the activity of intestinal disaccharidases.
Results showed a decrease in lactase activity in rats
fed saturated diets (coconut oil) compared to control.
However, polyunsaturated fat (corn oil) or fish oil
diets did not alter lactase activity. The high protein
diet (30% protein) reduced lactase activity and
resulted in low levels of total hexoses and sialic acid
content in brush borders of mice intestine82. The
imposition of undernutrition in weaning rats,
modulate the activities of various brush border
enzymes83. It is well established that lactase activity is
high and sucrase activity is almost absent during the
peri-natal period. The nutritional restrictions imposed
in suckling rats augmented lactase and diminished
sucrase activities, suggesting that maturational
development of these enzymes was delayed under
these conditions83.
Conflicting results of the effects of alcohol intake
on lactase activity have been reported. The lactase
activity is reported to decline in adult rats exposed to
30% ethanol [in drinking water (v/v)] for 3 months84.
Lactose intolerance is also manifested by poor
tolerance of dairy products, leading to low calcium
intake and poor calcium absorption from dairy
products. Increased bone turnover and decreased bone
mass have been reported, especially in men and
menopausal women, suffering from lactose
intolerance. This has been attributed to elevated levels
of bone turnover markers (urinary deoxy pyridinoline
cross-links) that were negatively correlated with total
daily calcium intake and positively correlated with
parathyroid hormone85.
A number of hormones influence lactase activity,
especially during the post-natal development.
Generally, pituitary and adrenal cortical hormones
enhance intestinal maturation during post-natal
development. Administration of thyroxine decreases
lactase activity in dose-dependent manner86. In
thyroxine-treated animals, lactase activity returns to
age-specific normal levels, before the low lactase
activity of adult rats was attained. Administration of
thyroxine to adult rats leads to the development of
villus hyperplasia and down-regulation of lactase
mRNA87. In adult rats, thyroxine specifically
decreases the amount of lactase, whereas the structure
of crypt-villus remains unaffected88. However,
Castillo et al89 demonstrated that in the absence of
thyroxine and growth hormone, the intestinal
maturation gets impaired, whereas lactase activity
remained abnormally high in 6 days-old pups.
The thyroxine injection soon after birth led to
decline in lactase activity in the colon than in the
jejunum in rats90. These findings have been confirmed
by comparing the lactase activity both in control
(injected with NaCl) and hormone-injected rats.
Administration of thyroxine soon after birth showed a
20% and 70% decrease in the lactase activity in
jejunum and colon respectively, in rats. In the
jejunum, thyroxine caused a 25% and 15% decline in
LPH-type proteins and LPH mRNA, respectively,
whereas in the colon, the LPH-type proteins as well as
the 6.3 kb mRNA were 3-fold less compared to
controls. However, exogenous administration of
epidermal growth factor (EGF) caused a slight
increase of specific activity of lactase, and the
amounts of LPH-type proteins and mRNA. In the
colon, in contrast, EGF injections caused
simultaneous decrease (70%) in 6.3 kb mRNA
transcript, LPH-type proteins and the specific activity
of lactase. Similarly, cortisone administration
increased both mRNA levels and lactase activities in
6 days-old pups, whereas the administration of
cortisone along with thyroxine antagonized the
enhancing effect of cortisone on lactase gene
expression90,91. In the absence of thyroxine, lactase
activity remained elevated in neo-natal rats and failed
to decline at weaning, while half-life of the enzyme
was doubled92.
Conclusions
It is apparent that multiple factors, such as (a)
decreased amount of lactase protein, (b) synthesis of
an inactive, high molecular weight lactase or defect in
post-translational modification of precursor lactase to
the mature enzyme, and (c) mRNA levels encoding
lactase are differentially altered and translated during
KAUR et al.: LACTOSE INTOLERANCE
post-natal development49, are involved in observed
decline and regulation of lactase activity in intestine.
The phenomenon of lactase expression is apparently
complex and multifactorial in nature. This needs
further studies to establish the precise mechanism of
hypolactasia in human populations.
Acknowledgement
We thank Indian Council of Medical Research,
New Delhi for the award of Senior Research
Fellowship to Ms. Kamaljit Kaur.
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