2. Physiology I Flashcards by J L

The Bile
• Bitter-tasting, dark green to ____ brown fluid, produced by the liver.
• Stored in the gallbladder and upon eating is discharged into the duodenum.

Physical properties;
Hepatic bile: pH ____, golden yellow.
Bladder bile: pH ____, green to dark yellow.
Volume of bile produced: up to 1 liter/day (depending on body size)

• Functions:
1. Enhancement of intestinal absorption:
• ____, calcium, iron.

Route of excretion of solutes poorly filtered by the kidney:
• Lipid-soluble compounds: ____, bilirubin, ____, plant sterols.
• ____-bound trace minerals.
• Antigen-antibody complexes.
• ____.
Secretion of ____- to neutralize any excess stomach acid before it enters the ileum.
____ action of bile salts on microbes ingested during meals.• When bile leaves hepatos > composition and acidity of the liver is around pH 7.4 (within psyiologic range of pH)
• Bile that leaves the gallbladder > changes color (change in composition) and in pH
• Most of recycled bile is ____ fluid (in terms of solutes)
• Hydrophobic/lipid soluble molecules can cross the membranes of cell easily > difficult to excrete through the ____ (immediately reabsorbed)
○ Bili eliminated via bile instead of kidney
• May contain high cxn of HCO3-
○ Physiology of GI tract > stomach makes food/fluids that’s high in acidity
○ Secretory of pancreas > bicarbonate; another source is also provided by the bile

yellowish

lipids
cholesterol
xenobiotics
protein
IgA
HCO3
bactericidal

recycled
kidney

How well did you know this?

Not at all

Perfectly

Biliary Tract: Liver Histology

Liver lobule is the basic functional unit of the liver:
• Hepatocytes:
• synthesis of ____ components.

Endothelial cells:
Lack a ____.
Facilitate exchanges between the ____ and the sinusoid.
Kupffer cells:
Monocyte/____ lineage: reticuloendothelial system.
Line the hepatic ____.• Hepatocytes are organized into hepato plates
○ ____ cells
§ One side is in contact with the space of Disse that is separated with endo cells from ciruclation
§ On the other side > domain forms a secretory duct
○ Hepatos can obtain from portal circulation > absorb and recycle > secrete substances into the bile canaliculus > bile excreted

bile
basal lamina
space of disse
macrophage
sinusoids

polarized

How well did you know this?

Not at all

Perfectly

Biliary Tract: Liver Histology

Bile is secreted in two stages:
1. Secretion by the hepatocytes into ____ located between rows of hepatocyte cells
(____).
2. The bile flows toward the ____, hepatic
duct and common bile duct.

• Important for recirculation of bile acid and salts

bile canaliculi
hepatic plates
bile ductules

How well did you know this?

Not at all

Perfectly

Biliary Tract: Hepatic Duct and Gallbladder

From the hepatic duct and common bile duct the bile either:
• Empties directly into the ____ at the sphincter of Oddi, or…
• Is diverted through the cystic duct into the
____: modification and concentration.

• Bile leaves liver through the bile duct > common hepatic duct > bile is directly excreted into the duo thorugh sphincter of Oddi, or stored in the gallbladder

duodenum

gallbladder

How well did you know this?

Not at all

Perfectly

The biliary tract has 4 components

• Canaliculus
	○ At level of hepatos > formation of bile > excreting bile into \_\_\_\_ (basal domain of hepato)
• Ductules &amp; ducts
	○ Passage thorugh the ducts > primary bile will be modified at the level of \_\_\_\_
	○ Composition of bile reaching and leaving is \_\_\_\_
	○ Secretion of \_\_\_\_ takes place
• Gallbladder
	○ Ion exchanges and absorption of water > \_\_\_\_ bile
	○ \_\_\_\_ delivery of the bile when its required for digestion
	○ During \_\_\_\_: stored in the gallbladder, and contracted and bile excreted through the sphincter of Oddi reaches the duodenum
• Sphincter of oddi
	○ Highly \_\_\_\_ in terms of opening/closing > prevents \_\_\_\_ of material from duo into the gallbladder

canaliculus
ion balance
different
bicarb

secondary
controlled
fasting
regulated
reflux

How well did you know this?

Not at all

Perfectly

Bile composition

• Don't memorize
• Composition of hepato bile and gallbladder bile is different
	○ Hepatic bile
		§ \_\_\_\_ cxn of solutes
	○ Gallbladder bile
		§ Relative cxn of solutes has \_\_\_\_
		§ High rate of water absorption in bile during the storage time
• Out of the solutes > mix of molecules
	○ Majority (2/3) is \_\_\_\_ > synthesized by the hepatos
	○ \_\_\_\_
	○ \_\_\_\_
	○ \_\_\_\_
	○ \_\_\_\_ products (bilirubin)
• Composition of solutes is constant in both, but the biles are different
	○ Gallbladder is more \_\_\_\_

lower
increased
bile acid
cholesterol
lipid
electrolytes
waste

cxn

How well did you know this?

Not at all

Perfectly

Bile Acids and Bile Salts

Bile acids:
Synthesized by hepatocytes from ____.
Secreted as conjugates of ____ or glycine.

• Classification:
• Primary:
• Synthesized by the \_\_\_\_.
• Examples: \_\_\_\_ acid and
\_\_\_\_ acid.

• Secondary:
• ____ of bile acids by GI bacteria.
• Examples: Cholic acid is converted to
____ acid and chenodeoxycholic acid to ____ acid.

cholesterol
taurine

hepatocyte
cholic
chenodeoxycholic

dehydroxylation
deoxycholic
lithocholic

How well did you know this?

Not at all

Perfectly

Bile acids and bile salts

• BA derive from cholesterol
	○ Complicated and long pathways
	○ Hepatos synthesize primary BA from cholesterol
• BA are divided into primary and secondary BA
	○ Primary > directly synth by the hepatos (chenodeoxycholic and cholic acid)
		§ When reach the colon > the bacterial flora will use some of the primary BA to modify them and produce > secondary bile acids (deoxycholic and lithocholic acid)
		§ Since the BA are continually recycled bt the GI and liver, eventually the bile that's stored in the gallbladder are \_\_\_\_ and \_\_\_\_
		§ Usually the primary BA produced by the liver are further modified to be secreted as conjugates
			□ Cholic acid has carboxy acid group; hepatos add taurine or glycine (AA) > glycocholic acid (conjugated)
				® Either conjugated or nonconjugated > still haevt eh \_\_\_\_ group at the end; most common species that you find in bile is the \_\_\_\_ form of acid that's balanced out by a + ion > most common presented as \_\_\_\_ (sodium glycolate, instead of glcyocholic acid)
				® The bile salts (ionized) are more \_\_\_\_ than free BA > much lower \_\_\_\_ across membranes then the case for the nonionized BA
				® When the bile salts reach the intestine > will not be efficient as crossing PM of enterocyte; the SI absorbs bile salts \_\_\_\_ than BA
				® Since bile salts have detergent function > to produce small globules of fat > and SI poor at absorbing BS > the lipids that are composing those droplets of fat + BS > the lipids are absorbed \_\_\_\_
				® The droplets of fat get smaller > the lipids are more \_\_\_\_ at being absorbed than the bile salt molecules
				® Only once all lipid absorbed > then \_\_\_\_ can cross the membrane (mostly do not cross by diffusion bc they're electrical, but there's a \_\_\_\_ located in the ileum)

primary
secondary

carboxyl
ionized
bile salt

polar
diffusion

slower
first

BS
transporter

How well did you know this?

Not at all

Perfectly

Bile Acids and Bile Salts
• Neutral pH: bile acids ionized to ____ (e.g. sodium cholate).
• Conjugated bile acids ____ more readily than the unconjugated bile acids (e.g., sodium glycocholate).
• Bile salts more polar than bile acids: lower ____
across cell membranes → Small intestine absorbs bile
salts much ____ than bile acids:
• Role in the intestinal absorption of lipid: smal intestine
absorb bile salts only after all of the ____ has been absorbed.

bile salts
ionize
diffusion
poorly
lipid

How well did you know this?

Not at all

Perfectly

Bile Acids and Bile Salts

• Detergent action:
• Emulsification of lipid particles in the food which
decreases the ____ of the particles.

Formation of micelles:
____ particles, 3-6 nm in diameter, 20-40 molecules of bile salt.
Transporters of monoglycerides and free fatty acids to the ____ of the enterocytes.
Hydrophilic sides positively charged due to ____ and other phospholipids → prevent bile salt-coated lipid droplets from aggregating into ____ particles: increased ____ for pancreatic lipase in lipid digestion.• BA/BS > detergent function
○ Ability of the molecules of BS to emulsify the globules of fat that is released during the digestion of the lipid-rich diet > convert into much smaller emulsified droplets
○ Where the fat globules cannot be referred to as dissolved in chyle, but emulsified molecules are essentially dissolved > more easily ____ to receptors and absorbed
○ Bc of their composition and of the fat > control the maximum size of mycelles
§ Two spheres > the smaller one has a higher ratio of ____
§ Since th elipids that form the spheres need to be degraded by panc lipase > needs a lot of surface > more efficient at digesting a ____ droplet than something like a fat globule
□ Bigger ball, surface:volume ratio is smaller

surface tension
colloidal
brush borders
lecithin
larger
surface area

attached
surface:volume
small

How well did you know this?

Not at all

Perfectly

Bile Formation: Canalicular Bile
• ____-dependent transporters.
• Bile salt secretion→ osmotic gradient→ water flow ____ the canaliculus.
• Ion exchanger: passage of ____- and ____- ions.

• Process of formation of the bile
• Hepatic bile > canalicular bile > primary bile by the hepatos
• Liver cell plates > substance being secreted
• Most of the substances secreted in the canaliculus > \_\_\_\_ org moleules (BA, phospho, glutathiamine) > secreted by transporters that are \_\_\_\_ (against their cxn gradient, and require ATP)
	○ Solution into canaliculus is becoming more \_\_\_\_
	○ When have the situation where the compartment is getting higher and higher > \_\_\_\_ of water into the canal bc of the inc of org substances
	○ At level of liver cell > secretion of bicarb in exchange for Cl-
		§ To balance the cxn of ions, since the \_\_\_\_+ ion is also being secreted by following the water

ATP
into
HCO3
Cl

large
active
cxn

influx
Na

How well did you know this?

Not at all

Perfectly

Bile Flow

Canalicular bile flow: sum of two components:

Bile acid–independent flow: “____” component ____ of bile acid secretion.
Bile acid–dependent flow: rising component that increases linearly with ____.• Measure flow of bile and relative composition > rate of excretion of BA vs the total flow of bile
• Looking at the canlaicular bile secretion; two flows:
○ BA independent
§ More or less constant independent of excretion of BA, whereas the flow that is depend on bile acid increases when the excretion rate of BA increase
○ BA dependent
§ When total excretion rate of BA increases (x-axis) > BA dependent flow is increasing, while the BA indepent is constant

constant
independent
bile acid secretion

How well did you know this?

Not at all

Perfectly

Bile formation: canalicular bile

• Two modes of hepatic bile secretion:

Bile Acid-Dependent Bile Flow:
[Na+] gradient created by the ____ (1)
Na+-dependent reabsorption of free ____ (2: Na+/BA symporter) and ____ before secretion.
Secretion: ____-dependent BA transporter(3).
BAs stimulate secretion of other solutes by trapping them in the lumen: ____, organic anions, ____ and phospholipids.
BA secretion → osmotic gradient → water flow ____ the canaliculus → bile flow.
Bile Acid-Independent Bile Flow.• Initial disequilibrium in ions is driven by the Na/K ATPase (a pump) that excretes Na and imports K > disequilibrium in cxn of Na
• In the hepato > have the synthesis of BA (new) that may/may not be conjugated; since most of the BA are recirculated bt the liver and intestine, some of the recirculated BA come back through the portal circulation and are reabsorbed by the hepatocyte > two components:
○ Small comoponet (from new molecules)
○ Large component > recirucaltion of bile salts
• The bile salts are asborbed with hepato in combination with Na+ > ____ transport
○ ____
• This absorption of bile acid is being drived by the Na/K ATPase
• Now have a pool of recycled Bile acids and new bile acid > (3) the ____ xport of bile acids (slide 13) is moving the bile acid into the canaliculus
• Bile acids will not only stimulate secretion of other solutes (by trapping them in the lumen), but most important > secretion of BA > ____ gradient
○ Inc OG > inc flow of water into canaliculus > flow of bile increases
• Without the reabsorption of BA from portal circ and rexporting bile acid > the amount of water entering canal would be ____, and the amount of flow depends on the rate of ____ being reabsorbed and reexcreted

Na/K ATPase
BAs
re-conjugation
ATP
bilirubin
cholesterol
into

symport
passive
active
osmotic
lower
BA

How well did you know this?

Not at all

Perfectly

Bile formation: canalicular bile

Two modes of hepatic bile secretion:
Bile Acid-Dependent Bile Flow.
Bile Acid-Independent Bile Flow:
Due to secretion of organic compounds, mainly ____.
Secretion of inorganic ions: ____- (5).
Energy provided by [Na+] gradient created by the ____ (1).
↑GSH → osmotic gradient → water flow ____ the canaliculus → solvent drag (↑____- ) → bile flow.• Na/K+ ATPase is present
• At the secretion of org molecules (glutathione) and bicarbonate
○ The energy that is provided depends on activity of Na/K+ ATPase
• For the secretion of bicarbonate > bc of the prod bicarb from Co2 and the ionization of carbonic acid into bicarb > ____ cahrge must be maintained, the protons derived from ionization are exported bc if you let the cxn of protons get high > low pH
○ Export of ____+ is balanced by absorption of Na+
○ Na+ follows cxn disequilibrium by the Na/K ATPase
• Org molecules will be secreted using ____ transport (____)
• Situation just like the dependent flow
○ The cell is secreting bicarb, and other org molecule
○ Inc cxn of solutes in canal > brings an inflow of water
§ The secretion of substances like GSH/bicarb is not at all dependent on the reciruclation/flow of ____

glutathione (GSH)
HCO3
Na/K ATPase
into
HCO3

electrical
H
active
MOAT

How well did you know this?

Not at all

Perfectly

Bile Modification in the Bile Duct

• Carried out by bile duct cells: ____.
• Similar to the secretion of ____- by pancreatic duct
cells.
• ↑HCO3- lumen → ↑____+ → osmotic gradient → water
flow.
• Result: ____ hepatic bile.

* Most impt modifcation of bile by epi cells that line the bile ductiles > cholangiocytes > is the secretion of bicarb in form of \_\_\_\_-bicarb
* Bicarb is being secreted, electrical charge of bicarb (negative) must be balanced by the secretion of Na+ ions > creates a \_\_\_\_ cxn gradient > water flow
* Most impt function of cells lining the bile duct is the secretion of \_\_\_\_

cholangiocytes
HCO3
Na
alkaline
Na
steeper
bicarb

How well did you know this?

Not at all

Perfectly

Bile Flow

• If we add the ____ secretion to the BA- dependent and BA-independent canalicular flow, which is also “constant,” we have the ____ bile flow

• Secretions produced by duct, is where you have total bile flow
	○ \_\_\_\_ secretion and \_\_\_\_ secretion > gives total bile flow
		§ Would be constant if it were not for the fact that BA-dependent flow depends on the \_\_\_\_ of bile acids

ductular
total
duct
canalicular
excretion rate

Gall Bladder Functions

• Physiological/biochemical problems of bile acids:

Detergent effect:
Potent lipid ____.
Strong ____ molecules toxic to enterocytes.
Loss from ____ intestinal transit.
Subject to chemical modification by____.
Gall bladder solutions:
Isolation of ____ from other GI organs, including liver.
Bile ____ mechanisms.
____ of the gall bladder tissue by secretion of mucins.
____ control of bile secretion in response to needs (meal/fasting).• Detergent effect > good at solubilizing lipids; unless stored in specialized compartment > would be good at solubilizing the ____ of the cells they get in contact with
○ Must isolate the molecules bc of the detergent effect
• Can be rapidly loss through their transit thorugh the intestine
○ If continuously secreted by the liver and sent to the intestine
• Used by intestinal bacteria as food, and subject to chemical modifications that some of them can be toxic to us
• Hepato produce more ____ bile > which avoids problems of inherent toxicity of bile acids; and gallbladder will cxn solute in an enviro where they remain isolated from gallbladder tissue itself by secretions of high levels of ____ by the gallbladder
○ Gallbladder tissue is protected from detergent action of BS
• By having the bile store in a diff compartment > can be controled in a fine manner depending on the needs of the body
• If all bile acid pool is going to derive from newly synthesized BA > the liver would not be able to ____ with the need for high cxn of BA acquired to assimilate fats

solubilizers
amphipathic

rapid
intestinal bacteria

bile acids
concentration
protection
neurohormonal

membranes
dilute
mucous
cope

Changes in Bile Composition during gallbladder storage

• Depending on the time at which the GB stores the bile from the liver; the \_\_\_\_ of BA and several \_\_\_\_ changes

• Loss of water by reabsorption, and by default > the cxn of most substances is \_\_\_\_ after storage in the gallbladder, compared to the cxn of those substances when they left the liver cell
• Some of the ions shown here like Na+, actually comes \_\_\_\_
• Bicarb really \_\_\_\_ in cxn
	○ In the gallbladder after storage will be lower
	○ The bile that is in storage > is more \_\_\_\_

cxn
ions
higher
down
drops
acidic

Mechanism of bile concentration by gallbladder epithelium

Major mechanism:
Water reabsorption:
Mostly ____: follows [____+] gradient created by the Na+/K+ ATPase at the ____ domain.
Decrease in [Na+] at the lumen induces the isotonic absorption of water through the ____ pathway and ____ transport of ____-.• Na/K ATPase creating the intiial Na+ disequilibrium and charge this equil by exporting Na+ ions into the interstitial side (BS) > the epi of the gallbladder creates a steep Na+ ion cxngradient > allows action of another ____ mechanism > Na+ absorbed from th elumen of the gallbladder in exchange for a proton derived from metabolism of CO2
• ____ in cxn of Na+ > induces absorption of H2O thorugh the paracellular pathway
○ Absorption of Na and ____ (to balance) induces the reasborption of H2O that’s cxning the bile in the gallbladder

passive
Na
basolateral
paracellular
passive
Cl

antiport
decrease
Cl

Enterohepatic Circulation of Bile Salts

Recycling of bile salts between the ____ and the liver.
Total bile acid pool: Total amount of bile acids in the ____, primary or secondary, ____ or free, at any time.
Bile acid hepatic synthesis rate: ____ mg/day
Bile acid secretion per meal: ____ mg/h
Recycled bile salts: ____ mg
Bile salts reused ~____ times
Fecal loss must be equivalent to hepatic ____ of bile acids at steady state.

small intestine
body
conjugated
200-400
2000-3000
2000
18
synthesis

Enterohepatic Circulation of Bile Salts

• We need per meal 2000-3000 mg/h (2-3) of digestion
• No way that synthesis of new BA by the liver would be able to produce enough BA for the digestion of the meal in the period in between meals
	○ 200-400 mg/day are synthesized, vs a required use of 2000-3000 mg/h when not fasting (when eating a meal)
• The total amount of BS in the total BA pool > \_\_\_\_ BS that adds about 2g
• If need bt 2000-3000 mg > total pool must be recycled once per hour/half-hour
• Total pool of BA (primary adnsecondary)
	○ Primary BA > comprise only 5% of the total molecules in that pool
	○ 95% of the BA have already been recycled
		§ Most are \_\_\_\_ bile acids
• The liver produces the bile acid and the primary ones > eventually reach the duodenum > emulsify fats and then reach the ileum > the micelles are now gone (reaborbed) and th eonly thigng left over is the BA > specific \_\_\_\_ to reabosrb the BS so they reach the portal circ going back to the liver
• Some of the BA that reach the ileum are not absorbed
	○ 5% of the 5% (only the primary)
	○ Reach the colon > bacterial flora > responsible for xforming the primary BA into \_\_\_\_ BA > reabsorbed in the LI and they will enter the portal circualtion so they can be recycled back to the liver
• Just \_\_\_\_% of the total pool of primary/secondary BA is lost in the feces
	○ Rate of loss is similar to the rate of \_\_\_\_ by the liver (5%)
	○ One of the reasons why the gallbladder is required > store the bile for further use when taking a meal, bc there is no way that the liver would be able to cope with such a demand of 2-3000 mg BS/hr bc the rate of synthesis is relatively low
• If the liver were able to make new primary BA on demand whenever we eat, and they were to be lost and not reabsorbed
	○ Problem with economy > synth of BA derives from cholesterol; cholesterol is \_\_\_\_ to make (complex pathway of the chol precursor itself, and then another pathway that goes from chol to BA [just as complicated, and just as energetically expensive)
	○ By having this enterohepatic circualtion > rate of synth is maintained \_\_\_\_, and not very \_\_\_\_ for body to produce the molecule

recycled
secondary
xporter
secondary
2-3
synthesis
expensive
low
expensive

Enterohepatic Circulation of Bile Salts
BS/BA in the intestine absorbed via four pathways into the portal circulation (enterohepatic circulation):
1. Passive diffusion of conjugated BS: ____ role.
2. Active transport of conjugated BS in the terminal
ileum: most ____ route.
3. De-conjugation to primary BAs by bacteria: ____
diffusion.
4. Conversion of primary BAs to secondary BAs by
bacteria: ____ diffusion.

1. Passive diffusion of conj BS
	a. Minor mechanism
	b. Bc the conj Bs are \_\_\_\_ cahrged, do not cross the PM very easily, and at this level there is no specific xporter for bile acids
2. ** active xport of conj BS in the terminal ileum
	a. Most important!
	b. Only region in SI that has high levels of xporters on surface of \_\_\_\_ and then released itno portal circ
3. In the intestine, some conj BS can be deconjugated to \_\_\_\_ BA by bacteria > can cross PM and not \_\_\_\_ charged and can be reabsorbed
4. Some of the BA reach the colon > place where formation of secondary BA (deoxycholic and lithocholic) > can be \_\_\_\_ from the colon through passive diffusion

minor
important
passive
passive

electrically
enterocytes
primary
electrical
reabsorbed

Regulation of Bile Secretion and Release

Main mechanism: ____ feedback – mainly on liver ____.
Bile acid/bile salt concentration ([BA]) in portal blood:
Synthesis from ____.
Bile acid-dependent secretion – recycling of ____.
Between meals:
Extremely ____ portal [BA] → ↑ ____ synthesis and ↓ BA-dependent ____.
Feeding:
High portal [BA] → ____ BA synthesis and ____ BA-dependent flow.
Secondary mechanisms: mainly on gallbladder ____.
Hormonal.
Neural.• Bt meals, the cxn of BA (BA + BS) in portal circ is very low > has been depleted from the last meal
○ During fasting the bile is not needed and does not need digestion and bile acid isn’t needed
○ But, the synth of BA by the liver is stimulated, whereas the flow of bile that is BA dependent is low
§ Low portal BA cxn > sends a signal to liver to inc ____ of BA
□ Feedback mechanism
• During the feeding > high portal BA cxn > increase in BA dependent flow, there is also an inhibition in the BA ____ in the hepato
○ The feedback: low BA cxn bt meals increases synth, or high BA cxn in the portal blood > inhibits BA synth

negative
secretion

cholesterol
BA

low
BA
flow

decrease
increase
release

synth
synthesis

Feedback Regulation of Bile Acid Synthesis
• Bile acids synthesized by hepatocytes from cholesterol.
• ____- and ____-catalyzed reactions:
• Reactions in the “____” bile acid synthesis pathway.
• ____ feedback based on bile acid concentration

• Summary of the synth of two primary BA (cholic and chinodeoxycholic acid)
	○ Very \_\_\_\_ in terms of energy
• Modification of cholesterol (precursor) following the classic pathway > formation of \_\_\_\_ acid
	○ Enzymes circled as cytochrome P450 7A1 and 8B1
		§ Essential for the pathway to function
		§ Feedback that activates/\_\_\_\_ > effective in regulating the synth of bile acids

CYP7A1
CYP8B1
classical
negative

expensive
cholic
inhibition

Feedback Regulation of Bile Acid Synthesis * Transcription factor ____ controls the adaptive response of the liver during the fasting- refeeding transition. * After a meal, BAs stored in the gallbladder are discharged into the intestine to stimulate absorption of ____. * BAs enter the enterohepatic circulation and return to ____ where they activate FXR. * Hepatic FXR inhibits BA synthesis by a feedback mechanism involving ____ and ____ (not shown) repression. * Ileal FXR induces ____ secretion, which in turn represses ____.

``` FXR lipids hepatocytes CYP7A1 CYP8B1 FGF19 CYP7A1 ```

Feedback Regulation of Bile Acid Synthesisi • Mechanism senses cxn of BA that are coming back to hepato from the portal circ and regulates action of one of two enzymes • The most important enzyme to remember is the ____ • When refeeding > digesting > will be an inc in BA in the intestine > will be an inc in cxn of BA in return ____ > more BA will reach the hepato > at high cxn of BA in the hepatocyte > BA (high cxn) activate ____ > can bind BA (they are farmacoid molecules, their chem property); FXR acts in conjunction with the ____ molecule • When FXR activated > inhibits cytochroe P450 enzyme (7A1) > rate of ____ of BA is decreased bc the cytochrome P450 enzyme has been inhibited by the farmacoid receptor • The neg feedback mech is to the presence of high cxn of BA; when the cxn of BA is low > farmacoid is not active > no ____ of cytochrome P450 enzyme > synthesis of bile acid increases • FXR also in the ____ > directly sense the cxn of BA that are being absorbed by the enterocyte > induces the produciton of ____ (growth factor) > circulation > reaches hepatocyte > signal transufction cascade > inactivates CP450 7A1 ○ High cxn of BA in ____ and ____ decreases rate of produciton of new BA • When there is flow of BA here > the hepatocyte needs to economize energy > the hepato tries to asborb as much as posisble of bile acids > recycled and resent to the intestine to asborb more fat ; hepato decides whether to take metbaolism to syntheiss or to circulation ○ During meals > ____; during fasting > ____

7A1 portal circ FXR small heterodimer synth inhibition ``` enterocytes enterocytes hepatocytes circulate synthesize ```

Regulation of Bile Secretion and Release: Hormonal Regulation • Hormonal regulation of bile secretion and release: gastrointestinal hormones. • Secretin: • Hormone secreted by ____ in response to acidic chyme. • Stimulates ____- and ____ secretion by bile duct cells. • cAMP signaling: phosphorylation of ____, opening of ____ and activation of the ____- exchanger AE2 • Neutralization of stomach acid in the small intestine. • Reduces effective [BA] in bile. • Regulating release of bile from GB, and also the composition • Back to the cholangiocytes > cells have receptors for hromones ○ Most important = secretin § Hormone produced by S cells in duodenum when the chyme is highly acidic > in addition to the targets within the GI tract, it can bind receptors in epithelial duct cells which regulates secretion of ____ § Signal trasn pathway of secretin works thorugh ____ pathway > protein kinase A (inc cAMP) > opening of the Cl- channel (CFDR) > ____ trans membrane conductance regulator (mutated in CF) > release of Cl- from the cell § Inc the Cl- cxn in the lumen of the duct > allows Cl-bicarb ____ to work efficiently □ More bicarb can be secreted in exchange for the Cl- ions that were released by the opening of the CFDR channel • Unclear that glucagon actually works this way

``` duodenal S cells HCO3 water PKA CFTR Cl/HCO3 ``` bicarb adenylate cyclase cystic fibrosis antiporter

Regulation of Bile Secretion and Release: Hormonal Regulation • Cholecystokinin (CCK): • Hormone secreted by ____ in response to ____ and amino acids in the chyme. • CCK stimulates the ____ to contract. CCK ____ the sphincter of Oddi to open. • When CCK reaches gallbladder or sphincter will mediate two diff actions ○ GB § Inc CCK > contraction of muscles in the gallbladder > inc flow of bile into the common bile duct ○ Sphincter of oddi § Relaxes the SM > sphincter opens • Together > ensures there's an inc in ____ of bile into the duodenum ○ ____; same hormone carries out ____ actions in these two targets

duodenal I cells fatty acids gallbladder relaxes flow coordinate reverse

Pressure in the distal biliary tract represents a dynamic interplay between secretion pressure, gallbladder compliance, & sphincter of oddi resistance • How different pressures allow release of bile from the GB • P1 - secretion pressure ○ Induced by ____ and ductile bile ○ Very ____! • P2 - ____compliance ○ ____ increases the pressure at wall of GB > squeeze the contents > bile leaves the GB towards the sphincter • At sphincter > CCK induces relaxation > P3 will be very ____ so the bile can leave the sphincter • For bile to reach the GB when it's being secreted by the liver and has been put into storage, pressure 3 has to be ____ than pressure at the bladder > bile will enter the GB • IF P2 > P3: when high levels of CCK > bile enters the ____ • If P3 is not 0 and is higher than P1: what if CCK is contracting the gallbladder but the sphincter is not opening > ____ ○ ____; the bile leaving the GB instead of going to the duodenum, it will go back to the liver • P2 and P3 must work in ____

``` canalicular low GB wall CCK low ``` higher cholestasis reflux concert

Regulation of Bile Secretion and Release: Hormonal Regulation • Gastrin: • Hormone secreted by ____ of the stomach in response to ____ in the antrum. • Direct effect: stimulation of hepatocytes to synthesize and secrete ____ – ____. • Indirect effect: stimulation of stomach parietal cells to secrete ____, inducing the release of ____ by duodenal S cells which stimulates ____- and water secretion by bile duct cells. • Steroid hormones: • Inhibition of bile ____ and secretion by the hepatocytes. • Indirect effect: estrogen reduces production of ____ by the pituitary, which reduces ____ activity in the liver. • Low bile secretion during ____. * The end effect of inc levels of circ steroid hormones > dec rate of BA synthesis by the liver * May be problems for pregnant women > when the cxn of steroid hormones (estrogens and progesterone) > will lead to low rates of bile secretion during pregnancy

``` G cells amino acids bile minor HCl secretin HCO3 ``` synthesis growth hormone hepatocyte liver

Regulation of Bile Secretion and Release: Neural Regulation * Parasympathetic (vagal) stimulation: * Gallbladder: * Release of ____: weak gallbladder contraction. * Sphincter of Oddi: * Release of ____ and ____: relaxation. * Liver: * Release of ____: small increase in bile synthesis. * Sympathetic stimulation: * Reduced ____ secretion. * Relaxation of the ____. • Most important neural regulation in terms of bile release > stim of parasymp system > the ____ nerve ○ Vagal nerve releases Ach § In response to the nutrients/AA/fats/pH in the duodenum > the duodenal cells produce CCK > direct action of CCK to contract Gb and relax sphincter § CCK can stimulate ____ aff pathways > induction of reflex by the vagal complex □ Through efferent nerves > vagal system responds releasing Ach at the level of GB, or NO and VIP at the sphincter □ So the sphincter ____ while the GB contracts □ The mechanism is the same bc it's just like the direct action of CCK that we saw before • ____ is minor compared to parasymp ○ Reverse to the parasymp ○ Reduced ____ of bile by hepatos ○ And prevent of any bile in storage

``` acetylcholine (ACh) nitric oxide (NO) vasoactive intestinal peptide (VIP) ``` ACh bile gallbladder ``` vagal vagal relaxes sympathetic secretion ```