Gastrointestinal System Lectures

PHPY 303.3
Lecture #7

Instructor: Dr. Francisco Cayabyab

Department of Surgery

Office: Rm. GD30.5 D-Wing,

Health Science Building

Tel: 966-8191

Email: frank.cayabyab@usask.ca
 Assimilation of Lipids,
Carbohydrates and
Proteins for Energy
Balance

Objectives
Describe events in small intestine that regulate digestion
and uptake of lipid, carbohydrate and protein digestion
by-products
Describe short-term and long-term regulation of feeding
behaviour
Regulation of Small
Intestinal Functions

Today, focus on lipid

digestion and transport
Next lecture, know ion
transport mechanisms for
Absorption of water and
salts
Secretion of water and
salts
 The Small Intestine Microvilli

Villi
Plicae circularis
Special structures
~600-fold in S.A.
Small Intestine
Crypts
Increased surface area for
5 GI Hormones:
digestion (brush border
CCK, GIP, Secretin,
enzymes), absorption and
Gastrin,
secretion
Motilin
 Small Intestine Motility
1. Segmentation Contractions
- Slowly mix and propel chyme
- Oscillating ring-like contractions
- Do not sweep the length unlike peristaltic
waves
- Initiated by pacesetter cells
- Increased by:
Distension
Hormone gastrin (from stomach)
Extrinsic nerve activity (parasymp)
2. Migrating Motility Complex
- Start when most meal absorbed
- Release of sm. intestinal hormone, motilin
- Strong repetitive peristaltic waves
- From the stomach to end of small
intestine
- Sweep remaining contents towards the
large intestine (colon)
 Food Molecules are Digested by
Hydrolysis Reactions and Absorbed
Digestive enzymes hydrolyze
food molecules into their
subunits
Monosaccharides, amino
acids, fatty acids, glycerol
Monosaccharides and amino
acids transported directly into
capillaries within villi
Fat released into lacteals
within villi and transported via
lymphatic system
Barriers to Nutrient Assimilation

Mucosal Barrier to Absorption

1. Unstirred layer of fluid
2. Glycocalyx (fuzzy coat)
3. Cell membrane
4. Cytoplasm of enterocyte
5. Basal or lateral cell membrane
6. Intercellular space
7. Basement membrane
8. Membrane of capillary or lymph

Water-soluble nutrients, protein and carbs, require

special mechanisms to facilitate transport across
enterocyte apical membrane
In contrast, products of lipid digestion, readily cross cell
membranes for absorption into body (but require
incorporation into micelles)
 Lipid Assimilation
Gastric vs. Pancreatic lipases
Importance of hormone CCK
Role of bile acids and micelles
Transport of lipid by-products in
chylomicrons
 Lipids: Role and Significance
Hydrophobic substances (insoluble in aqueous
solution, not readily absorbed)
Very important part of human diet
Denser in calories than proteins or carbs (Fat>>Prot>Carb)
Several vitamins are lipids (Vit. A, D, E and K)
Lipids enter epithelial cells largely by passive
diffusion, depending on following processes:
Secretion of bile and various lipases
Emulsification
Enzymatic hydrolysis of ester linkages (TG to FA and Glyc)
Solubilization of lipolytic products within bile salt micelles
Liver Secretions

Primary bile acid

(liver, conjugated with taurine, glycine)
Secondary bile acid
(colonic bacteria enzymes, deconjugated)
 Bilirubin (Bile Pigment)
Produced in liver, spleen, and bone marrow
from heme groups (minus the iron) of
hemoglobin
Not very water soluble, bound to plasma
proteins when circulates in blood
Liver removes some bilirubin and conjugates
(combines) it with glucuronic acid, forming
conjugated bilirubin (secreted into bile)
 Enterohepatic Circulation of
Urobilinogen
Bacteria in intestine
convert bilirubin (bile
pigment) into
urobilinogen
Some urobilinogen
excreted in feces;
some absorbed by
intestine, to be
recycled through liver
Some of absorbed
urobilinogen enters
circulation and gets
filtered by kidneys
into urine (gives urine
Conjugated
yellowish brown
colour)
 Structure of Bile Components
Bile acids (from cholesterol),
50% of solid components of
bile, e.g., cholate
polar hydroxyl group (dark
green) and carboxyl group on
(trihydroxyl group) same side
Chenodeoxycholic acid/deoxycholic acid
Aggregate as conc. increases,
Lithocholic acid (monohydroxy slightly soluble) aggregates called micelles
formed when critical micellar
concentration reached
Phospholipids, next most
abundant organic compound,
e.g., lecithin
Polar phosphatidylcholine
group and nonpolar fatty acids
are at opposite ends
Cholesterol, small amounts
(4% of total solid bile)
only one hydroxyl group
present, thus strongly
hydrophobic (insoluble)
Also bile pigments, inorganic ions
 Bile Acids Form Micelles
When bile acid bound to amino acids taurine and
Glycine, form bile salts
Liver converts cholesterol into bile
acids (e.g., cholic acid)
Aids in digestion
Major way for cholesterol excretion
Part of bile acid molecule is polar
(have OH-group), but most is
nonpolar
Emulsification of large fat globules
Into smaller droplets
Bile acids in water aggregate to
form associations called micelles
Cholesterol and lecithin, being
nonpolar, can enter micelles
Bile acids in micelles emulsify
triglycerides (fats and oils) in the
chyme
Primary Bile Acids (Liver) and Secondary
Bile Acids (Colonic Bacteria)
Bile acids from
cholesterol synthesized
by hepatocytes (200-
400 mg/day in humans)
Rate limiting step is
hydroxylation of
cholesterol
Primary bile acid
synthesis in liver,
whereas secondary bile
acid produced in colon
by bacterial enzymes
Lithocholic acid very toxic
 Bile Acid Conjugation
pKa=pH at which [HA]=[A-]
[HA], conc. of unionized acid
[A-], conc. of ionized acid
Primary bile acids (e.g.,
cholic acid) conjugated to
either glycine or taurine in
hepatocytes
Conjugation renders bile
acids more water-soluble
These conjugated bile
acids then actively
transported across
canalicular membranes
Bacteria deconjugate
both primary and
secondary bile acids
(more lipophilic), which
can be passively
absorbed in intestine and
later reconjugated in
hepatocytes
 Enterohepatic Circulation of Conjugated Bile Acids

Emulsification

Enterohepatic circulation
of bile salt conjugates
(secondary deconjugates)

asbt =
Apical sodium-dependent
bile salt transporter

Where does 0.2 g/day of bile in large intestine go?

Colonic bacteria deconjugate bile salts (becomes secondary bile acids), which are
lipophilic and are readily reabsorbed by colonic epithelium.
Pathways for Solute Entry into Bile

Either active secretion

involving specific
transport proteins in
canalicular
membranes
(drugs) Or passive
permeation through
tight junctions linking
adjacent hepatocytes
 Hepatocyte Transporters

***

***

***

***Need to be familiar for exam!

 Lipid Digestion I: Gastric Lipase
Gastric lipase from chief cells Hydrocarbon chains
Gastric lipolysis is incomplete,
10-30% of overall lipolysis in
healthy adult stomach
Gastric lipase displays a pH
optimum of 4.0-5.5
Resistant to action of pepsin
Acts preferentially to
Triglyceride molecule not
hydrolyze fatty acid linked to
fully broken down to its
first position of triglyceride
component parts
(outer ester linkages)
Except for short-chain
fatty acids, no absorption
Know difference between of fat from stomach
Gastric vs. Pancreatic Lipases for EXAM!!
 Lipid Digestion II: Intestinal Digestion

Meal moves from acidic

gastric environment to
that of small intestine
Actions of CCK
slows gastric motility
and emptying
also stimulates
pancreatic enzyme
secretion (lipase),
contracts gallbladder,
and relaxes sphincter Pancreatic lipase
Cleaves off first and third fatty acids,
of Oddi
gives monoglyceride and free fatty acids
Fatty acids are potent pH optimum in neutral range
stimuli of CCK release Inhibited by bile acids (like gastric
lipase)
 Role of Bile Acids/Micelles

(conjugated bile acids to glycine or taurine)

Gallbladder contracts, release of concd. bile salts, fatty acids and

monoglycerides move into micelles formed by bile salts secreted by liver
Epithelial Events in Lipid Assimilation.
Brush Border Events
Products of fat digestion held
in solution in micellar state,
combined with bile salts and
phospholipids
As fatty acids are absorbed,
more can be released from
micelles
Diffusion through unstirred
layer only occurs for very
small particles (micelles) or
molecules in solution (not for
fat drops)
Micelle does not fuse with cell
membrane, rather digestion
products exchange from
micelle to cell
 Mixed Micelle Formation
Lipase digests/hydrolyses
emulsified fat droplets (1)
Bile acids displace lipase (2),
inhibiting lipolysis
Lipid digestion by lipase
facilitated by colipase
Colipase binds both bile
acids and lipase (3), and
positions lipase near
oil/water interface
Colipase facilitates transfer
of lipid digestion products
from fat drop into micelle
Secretion of Chylomicron by Epithelial Cells
Absorbed fatty acid (FA) and
monoglyceride (MG) are
reesterified to form triglyceride
(TG) in smooth ER.
Apolipoproteins synthesized in
rough ER and glycosylated,
then coated around lipid cores
and secreted from basolateral
pole via exocytosis
Chylomicrons, mainly triglycerides
and phospholipids coated with
apolipoproteins
Contains small amount of
cholesterol and cholesterol esters
in center
diffuse into lymphatic sacs, move
along with lymphatic fluid back into
general circulation (thoracic duct
then joins venous blood)
Absorption of Fat Soluble Vitamins
Such vitamins solubilized in micelles, re-esterified in
enterocyte, and incorporated into developing
chylomicron
Hepatic stellate cells serve as reservoir for vitamin A
(exists as retinol, -carotene, retinal)
Vitamin D absorbed mainly in jejunum, transported in
chylomicron to kidney and liver for activation
Vitamin E incorporated into chylomicrons, enters
lymphatic system, functions as anti-oxidant
Vitamin K1 and K2 enter lymphatic system; involved in
synthesis of blood clotting factors
Vitamin D Synthesis and Activation
Vitamin D precursor 7-dehydrocholesterol from
animal tissue (ergosterol from plants) absorbed
in gut, stored in skin
Photolysis of precursor by sunshine radiation to
vitamin D3 or cholecalciferol (plant version
becomes vitamin D2 or ergocalciferol)
Liver modification to 25-hydroxycholecalciferol
(aka, 25OHD3 or calcidiol); P-450-containing
oxidases and hydroxylases (CYP27A1)
Then to kidney for final activation to 1,25
dihydroxylcholecaciferol (aka, 1,25(OH)2D3 or
calcitriol); hydroxylase CYP27B1
Pathophysiology and Clinical Correlations
Decreased Fat Digestion
Pancreatic insufficiency
Output of pancreatic enzymes grossly reduced
Malabsorption of lipids and fat-soluble vitamins
Congenital Lipase Deficiency
Impaired lipid assimilation
Administration of pancreatic enzyme supplements
Enzyme Inactivation
Pancreatic lipase sensitive to low pH
Patients with secreting gastrinoma (Zollinger-Ellison Syndrome),
enhanced gastric acid secretion, impaired lipolysis
Decreased Absorption
Bile acid malabsorption
Fall in luminal bile acids, due to bile outflow obstruction (stones)
or resection of terminal ileum (interrupt enterohepatic circulation)
Deficiencies in fat soluble vitamins