Lecture 2 Flashcards
Lactose intolerance intro
- Lactose is not broken down in the small intestine so it reaches the colon
- in the colon, lactose cannot be digested:
- no lactase enzyme expression in the colon - only has microbial lactose fermentation
- microbiota ferments the non digested lactose in the colon - leads to classic symptoms
Carb classification
Simple Cho: 1 or 2 monosaccharides linked by a glycosidic bond
Monosaccharides: glucose, galactose, fructose
Disaccharides:
- lactose(= glucose + galactose)
- Maltose
- sucrose
Lactase hydrolysis in small intestine (expressed in jejunum & ileum ) produces above reaction
- Lactase: enzyme
Lactose: disaccharide
*midterm q?: enzyme / catalyst of disaccharides:
( Maltase, sucrase, lactase)
Monosaccharide absorption review
- Enterocyle / epithelial cells (intestinal cells that line brush boarder
- two boarders must be crossed to enter the bloodstream:
- apical border
- basolateral border - Glucose & galactose cross the apical border via SGLT1 ( sodium glucose linked transporter-1) by c0 transport with 2 Na+ ( bothusing same transporter)
- a sodium potassium pump maintains the Na+ conc gradient ( relies on sodium) - Fructose cross apical border via GLUT5 byfacilitated diffusion (DOESNT rely on sodium)
- GLUT2 is the transporter for all monosaccharides on base lateral border (facilitated diffusion)
Absorption (transport ) of monosaccharides
In si:
1. Active transport of Na from enterocyte to blood: removal of na+ from inside the cell maintains the concentration gradient
2. SGLT1 co transporter needs both Na+ and glucose to work: 2 Na+ and 1 glucose/galactose enters cell
3. GLUT2 = facilitated diffusion of glucose into blood
4. For SLGT1 to keep functioning we need to continuosy remove Na from inside cell ( ongoing activity of Na/K pump)
- fructose uses GLUT5 instead of SLGT1 on apical membrane
Galactose is transported the exact same way as glucose
Fructose malabsorption
- Caused by deficiency in GLUT5 in small intestine ( can’t be transported), NOT fatal
- not to be confused with fructose intolerance: liver aldolase B not expressed → F1P accumulates, fatal
Lactose intolerance etiology
Inability to break down lactose in si due to loss of lactase enzyme expression: lactose enters colon
- Primary lactase deficiency ( inherited ): loss of lactase expression after weaning, irreversible
- congenital lactase deficiency rare - Secondary lactase deficiency (acquired): loss of lactase expression due to gi mucosal injury damaging brush border of si, reversible
- children: gastroenteritis
lactose intolerance perspectives
- in most infants intestinal lactase activity is maximal during perinatal period BUT 1 of 2 groups emerge from 2-12:
1. Lactase non-persistance (lactose intolerance): WILDTYPE (normal, 70%), low lactase activity due to - - low lactase gene expression
- low lactase protein expression
- low enzymatic activity of lactase protein
- lactase persistence: mutants, retain neonatal lactase activity into adulthood, (lactase persistence can still decrease overtime though)
why do certain populations tend to have higher prevalence of lactose intolerance
- SNPs cause genetic variation
- SNPs associated with lactase persistence phenotype (mutant) (having the SNP = lactose tolerant)
- SNPs located in lactase neighbour MCM6 in a regulatory region that influences lactase promoter and control lactase gene expression (LCT) and transcription
SNPs are COMMON in white populations:
- intron 13 of the MCM6 gene: C to T switch
- intron 9 of the MCM6 gene: G to A switch
SNPs are RARE in asian and african populations:
- different SNPs and rarer
SNPs are highly correlated with lactose intolerance
- C to C: lactose non persistance
- C to T: lactose persistence (dominant allele)
wildtype: NO SNPs (two C to C alleles)
lactase persistant:
- one SNP (one C to C allele and one C to T allele) OR
- two SNP (MUTANT): two C to T alleles
creates spectrum of symptoms
additional level of regulation of Lactase (LCT) gene expression
“base amount of lactase activity comes from SNPs then:”
- two transcription factors that activate LCT transcription (lactase persistence): Cdx2 and HNF-1a
- PDX-1: transcriptional repressor that blocks Cdx2 and HNF-1a (independent of SNPs and lactase gene)
- results in no or reduced LCT transcription
LOW PDX1: LCT gene expressed
HIGH PDX1: LCT gene repressed
midterm question
reasons why we see a spectrum of LI and symptoms
reasons why we see a spectrum of LI and symptoms
- differences in microbiota and amount of fermentation/ types of acids and gases produced
- types of food eaten and food matrix
- SNP variability, transcription factors (Cdx2, HNF-1a, PDX-1)
