Remember that the stem cells of the GI tract are located in the intestinal crypts and they migrate up the villi to differentiate into enterocytes, goblet cells, or endocrine cells. Also cells can migrate down the villi to differentiate into pana cells, defense cells
Remember that cells in the crypts are mostly secretory and the cells in the villus are more absorptive
T or F. There is a very high proliferation rate in the intestine
T. Very 3-5 days all cells will replace themselves as a protective mechanism against damage/mutation
Trypsin breaks carboxyl terminal bonds of basic peptides like arginine and lysine
chymotrypsin breaks N-terminus bonds of aromatic AA bonds (elastase is similar but broader)
Note that there are two main categories/locations of digestion in the Gi tract, lumenal digestion which is mediated by secreted enzymes mainly from the pancreas, and membrane-digestion which is mainly mediated by brush-border dissaccharidases such as maltase, sucrase, lactase, etc.
What are the main layers/barriers that a molecule must pass to be absorbed from the GI tract?
1. The undisturbed mucosal layer
2. The glycocalyx layer
3. The epithelium, cytoplasm, and then basolateral membrane
What are the main mechanisms of GI absorption?
1) Pinocytosis- simple invagination of the epithelium of the villi (very little). Note that proteins mostly arent absorbed by the small intestine, but those that are, are mediated by pinocytosis
2) Passive diffusion via paracellular (leakly in small intestine) routes for only some molecules (semi-permeable)
3) Facilitated diffusion
4) Active transport (Na, sugars, AAs)
How does the GI respond to starvation or resection?
During starvation the villi shorten and some digestive enzymes do not proliferate, but during resection you will initially see undernutrition but the remaining tissue will expand and adapt
Malnutrition doesnt really occur until 70% of the small intestine is removed/damaged
Digestion of carbs
Luminal digestion of carbs is mediated by salivary a-amylase in the mouth (break a1,4-glycosidic bonds to form maltose, maltotriose, and limit dextrin) and pancreatic a-amylase in the small intestine
Membrane digestion is mediated by glucoamylase, sucrase, isomaltase, lactase, and trehalase
Note that the body has a very high carb digestive capacity so that pretty much everything we eat is digested
What are the main products of GI digestion to be absorbed?
The vast majority of glucose absorption is aerobic and via active transport
How is glucose absorbed from the GI lumen?
1) SGLT 1, which is a Na/Glucose co-transporter that depends on a gradient of sodium which is maintained by active sodium transporters on the BL membrane
2) GLUT 2-BL (glucose, galactose, and fructose) and 5-apical (glucose and fructose). These are Na independent (more facilitated than active)
These have a VERY high absorptive capacity (and is not very regulated- dont overdo it)
Sucrase-Isomaltase normally presents in children because they only express lactase in early childhood and then switch primarily to sucrase-isomaltase expression and this can occur when the timing messes up
B: Absence of SGLT2
C: Overall impaired absorption
How much protein are adults exposed to on a normal day?
About 100g dietary and another 40g from secretions, cellular degeneration, etc. Note that all of this is acted upon by proteases in the GI lumen
How is trypsinogen secreted from the pancreas activated?
Once it reaches the duodenum, enterokinase from duodenal cells cleaves a 6 AA residue from the C-terminal end to produce active trypsin. Trypsin then activates the other pancreatic enzymes, as well as more trypsin
What predominantly causes acute pancreatitis? Chronic?
Acute: Biliary obstruction and alcohol
What is the mechanism of pancreatitis?
there is premature activation of trypsin in the pancreas caused by interaction of trypsinogen with pancreatic lysosomes (which contain enterokinase) or genetically due to a R117H mutation (prevents inactivation/stabilizes) that causes pancreatic destruction
There are many types of free AA transporters including Na dependent transporters, PAF proteins (driven by NHE) and facilitated diffusion as well, specific for basic, acidic, neutral AAs
Large peptides are broken down further by brush border peptidases
Note that the absorptive capacity of di- and tripeptides is greater than that of free AAs suggesting seperate carrier systems for them, predominantly in the proximal intestine (whereas free AA transporters are more clustered in the distal small intestine). These are coupled to NHE
Note that if you present arginine as a dipeptide it will be absorbed better b/c its absorbed using a different transporter
How is fat absorbed?
This requires the presence of bile and lipases and emulsification (breaking down for action with lipases). Lipases include gastric lipase (breaks down the fatty acid/glycerol bond at position 3) producing diglycerides
Monoglycerides and free fatty acids can be absorbed
What are the products of lipids being hydrolyzed by lipases?
What happens to the monoglycerides, fatty acids, and cholesterol?
They form mixed micellese are diffuse across the lumenal membrane via passive diffusion (may be facilitated), but the entire micelles are not absorbed all together so the carriers may be different
Once in the cytosol, these particles are insoluble again and are transported by binding to fatty acid binding proteins to the smooth ER where the triglycerides are re-synthesized using acyl CoA and ATP and then packaged into chylomicrons
How are chylomicrons produced in the small intestine?
They are composed of mostly TAGs and they are formed via 2 parts:
1) Formation of a particle 1 (Apo-B + core lipid) formed in the RER
2) Particle 2 is formed in the SER
3) These particles combine to form a pre-chylomicron
The pre-chylomicron that budds of the ER using a PCTV and acquires a Apo-A1 in the golgi, and then is exocytosed into lymph (not blood like carbs and proteins)
What are some conditions that lead to steatorrhea?
1. Rapid gastric emptying
2. Defect in pancreatic enzyme secretions
3. Interrupted enteroheaptic circulation (bile is needed to solublize lipids for absorption!!)
4. Qualitative deficit of bile acids
5. Inadequate chylomicron formation or Defect in lymph transport of chylomicrons (both lead to backflux)
Why would rapid gastric emptying lead to steatorrhea?
Pumping that much acid into the duodenum can overcome the neutralzation by HCO3- and pancreatic enzymes cannot be activated in too low of pH
How are most fat and soluble vitamins absorbed?
passively, with fat soluble vitamins such as A,D,E, and K forming bile salt mixed micelles for absorption
Which vitamins require Na-dependent active transport for GI absorption?
Thiamine B1), Vit C, folate (Duo and upper jej), B12 (ileum)
How is riboflavin (B2) absorbed?
How is calcium absorbed from the GI?
via channels like TRPV, voltage gated, and then calcium binds to CaBP (calbindin) for transport across the cell to the BL membrane where it is absorbed via CaATPase (active)
NOTE: VitD (via PTH) upregulates transcription of CaBP
How is iron absorbed form the GI?
In the villi region there is a transporter called DMT1 for Fe2+ (Fe3+-ferric cannot be absorbed- Fe3+ can be converted to Fe2+ via DCYTB) that absorbs iron. Iron is then bound to transferrin and either stored as ferritin or transported into blood via ferroprotein-1 (FPN1)
Also in the crypt region of the GI, there is a Fe-transferrin apical receptor for internalization (the receptor recycles)
Almost all fluid is reabsorbed!! Dont want to be shitting everywhere
Note that there are two main paracellular pathways- leaky and pore pathways. The pore pathway is mediated by Claudins, like claudin 2 in the duodenum and proximal jejunem which allows passage of Na+ and K+ (cations). So most Na and K is absorbed in the proximal intestine where the Cldn 2 molecules are, mainly driven by hydrostatic and osmotic gradients from food/drink
Na can also be absorbed transcellularly from the apical membrane driven by a BL Na/KATPase and via co-transporters (e.g. Na/Cl and Na/glucose), as well as NHEs (D)
A, B, and D are mostly found in the proximal intestine and C is found mostly in the distal
This occurs predominantly in the very distal ileum and colon (this is why the GI tract becomes more alkaline as it approaches the colon)
Note that distally induced diarrhea would lead to metabolic acidosis unlike vomiting
In the colon K+ is actually secreted. So K+ will also be lost in diarrhea
Water is absorbed primarily via an osmtoic gradient as Na and K are absorbed. Note that the GI lumen is almost iso-osmolar to the blood in the duodenum and becomes hypo-osmolar in the distal GI due to the efficiency of Na and K absorption in the proximal GI
Diffusion of water, Na, or K does not occur in the colon
T or F. In the small intestine, the net effect of the absorption AND secretion of electrolytes like Na and K is absorption
T. Although both occur
Secretion of electrolytes in the small intestine
A: VIP, Secretin, prostaglandins- all icnrease secretion of Cl-
___% of pancreatic lipase has to be dysfunctional/absent to cause steaorrhea
80%. This is a trend with the GI in that it typically takes a large decrease/increase/dysfunction of something to change the status-quo of absorption/digestion/secretion/etc.
Insulin (like leptin from adipocytes) reduces food intake by acting directly at the hypothalamus!
How does insulin affect appetite and metabolism?
It acts on the hypothalamus to decrease appetite and increase metabolism
How does leptin affect appetite and metabolism?
it acts on the hypothalamus to downregulate NPY, AgRP and upregulate POMC to promote decreased appetitie and increased metabolism
How does CCK affect appetite and metabolism?
It is released from I cells of the duodenum to act on vagal affarents to the brain to decrease appetite and decrease gastric emptying (increases satiety)
How does PYY affect appetite and metabolism?
It is secreted by L cells of the ileum and colon and acts on the hypothalamus to downregulate NPY and AgRP and upregulate POMC to promote decreased appetite and increase gastric emptying
How does ghrelin affect appetite and metabolism?
it is released from endocrine cells of the oxyntic gland area of the stomach and acts on the hypothalamus to upregulate the NPY and AgRP neurons to promote increased appetite and decreased gastric emptying (the exact opposite of PYY)