13-1: 2/7 - Liver Physiology

Front 1

Nutrient-rich blood is delivered to the liver via this vessel.

Back 1

Portal vein

Note: portal vein arises from stomach, intestines, pancreas, spleen; BLOOD FROM GI TRACT DRAINS TO PORTAL VEIN

Front 2

What is a Kupffer cell?

Back 2

Resident mac of liver; screens out unwanted substrates/toxins from intestines

Front 3

What is a Stellate cell?

Back 3

Cell involved in liver repair/regeneration, deposits collagen(?) in response to injury

Front 4

What is unique about enterohepatic circulation?

Back 4

Enterohepatic circulation of solutes (esp bile salts) is a closed loop, i.e., solutes taken up by intestine and returend directly to liver via splanchnic circulation for resecretion. Doesn't need to go to systemic circulation!

Front 5

What are the major functions of the liver?

Back 5

Regulate energy metabolism (carbs, lipids, proteins)

Detox and elimination

Bile production

Storage of vits, trace elements

Front 6

The majority of glucose is stored as ________.

What about excess glucose?

Back 6

Majority of glucose stored as glycogen in liver.

Excess glucose converted to FAs and secreted as VLDL for storage in adipocytes.

Front 7

How does the liver respond to a post-prandial state?

Back 7

1) Liver adds glucose to blood rather than removing it. Glycogen broken down to glucose to supply brain (glycogenolysis), RBCs. Liver is sole source of glucose in postasborptive state!

2) Adipose tissue releases FAs. Replaces glucose as fuel for most tissues. GLUCONEOGENESIS

Front 8

Why is hypoglycemia seen in liver disease?

Back 8

Acute liver failure-->impaired glucose production (dec'd glycogenolysis, glucneo)

Front 9

Why is hyperglycemia seen in liver disease?

Back 9

Cirrhosis!

Impaired non-oxidative utilization of glucose, dec'd storage of glycogen.

Impaired uptake of glucose by muscle.

Causes insulin-resistant state ~to pts w/DM.

Front 10

What role does the liver play in lipid production/metabolism?

Back 10

1) Synthesizes TGs from carbs/prots

2) Oxidizes FAs to supply energy

3) Synthesizes other lipids (chol, phospholipids) and lipoprots

Front 11

This yields the highest ATP production of any metabolic fuel.

Back 11

Oxidation of FAs

Front 12

FA/TG Synthesis:
Where does it occur?
Under what conditions?
Describe synthesis.

Back 12

Occurs in cytosol in hepatocytes

When liver is saturated with glycogen, excess glucose shunted to this PW.

FA is esterified w/glycerol-->TGs

TGs carried via lipoprots (VLDL) to distal sites for storage/use

Front 13

How are fatty acids used for energy?

Back 13

FA-->beta-oxidation-->acetyl-CoA-->-->ATP

Front 14

Non-Alcoholic Fatty Liver Disease:
What is it?
Populations affected?

Back 14

Excessive fat retention in liver; common in pts w/obesity, DM II, metabolic syndrome

Front 15

Describe the metabolic PWs leading to fatty liver disease.

Back 15

1) excess ingestion of fat in diet-->enters liver as chylomicrons (inc'd FA delivery to liver)

2) Inc'd breakdown of TGs in fat tissue and inc'd delivery of FA to liver--typically shut off by insulin, but with obesity, there is insulin-resistance and leads to continual breakdown of TGs and delivery to liver.

3) Upregulation of SREBP, CHREBP transcription factors (seen in DM II, insulin-resistance): inc'd FA production in liver

End product of all processes = inc'd FA retention in liver

4) Liver can get rid of excess fat in 2 ways: esterificaiton (pack into VLDL to store in adipose tissue), beta-oxidation (burn off fat). Reduction in packaging of TGs (and expert via VLDL), and beta-oxidation in pts with obesity. This damages liver and can result in cirrhosis/end-stage liver dz.

Front 16

What are the three major sources of cholesterol?

Back 16

Dietary cholesterol as chylomicrons

De novo synthesis (by liver)

Uptake from circulation (as LDL)

Front 17

What are the possible fates of cholesterol?

Back 17

1) Secretion into bile (synthesis of bile acids, excretion of cholesterol)

2) Export to blood in form of VLDLs

3) Steroid hormone synthesis (adrenocortical hormones, PG, E2, T)

ALL DONE BY LIVER

Front 18

Lipoproteins:
Function

Back 18

Function as vehicles to transport lipids in blood in form of soluble complexes of lipids and proteins (fat is not soluble in blood!)

Front 19

Chylomicron:
Function

Back 19

Transports FAs from GI tract (very high fat content) to adipocytes/muscle and to liver

Front 20

Beginning with cholesterol in the gut, describe the possible fates of cholesterol.

Back 20

Cholesterol-->poop out

Cholesterol-->chylomicrons--> adipocytes/muscle or liver

In liver-->Bile acids (back to gut) or TG/Chol/Chol-E

If TG, etc-->VLDL-->adipocytes, muscle--LDL (leftover cholesterol)-->back to liver

Front 21

What roles does the liver play in protein metabolism?

Back 21

1) Deamination of aa's

2) Removal of ammonia from systemic circuln by formation of urea

3) Formation of plasma prots (albumin)

4) Synthesis of aa's and other cmpds from aa's

Front 22

Ammonia:
How is it formed in body?
Why must it be removed from blood stream?
How is this accomplished?

Back 22

Ammonia is byproduct of COLONIC bacteria, renal production

It is toxic to CNS and must be removed

Delivered to liver via portal vein; liver converts it to glutamate, glutamine, and UREA

Front 23

Why must amino acids be deaminated?

How does this occur?

Back 23

Deamination required before AAs can be used for energy or converted to carbs/fats

Requires aminotransferases, ALT (alanine), AST (asparate)

Front 24

Under what conditions is serum ammonia elevated?

Consequences?

Back 24

Impaired removal of ammonia from blood due to liver failure.

Consequences:
Hepatic encephalopathy
Hepatic coma

Front 25

90% of plasma proteins are produced in the _______.

What is the major exception?

Back 25

90% of plasma prots formed by liver

Exception is immunoglobulins

Front 26

What major plasma proteins are synthesized by the liver?
Roles of each?
Effect of deficiency?

Back 26

Albumin: maintains osmotic pressure of plasma (edema)

Clotting factors (V, VII, IX, X, XI, II)--deficiency-->easy brusing/hemorrhage

Fibrinolysis factors (thrombosis)

Front 27

Beginning with hepatocyte import, describe the steps by which toxins are removed via the liver.

Back 27

Hepatocyte imports compound from blood across basolateral (sinusoid) membrane

Hepatocyte chemically modifies/degrades compound intracellularly

Hepatocyte excrete molecule or product into bile bile across apical (canalicular) membrane for excretion into feces

Front 28

What is the bile canaliculus?
Function?
Describe all steps.

Back 28

Bile canaliculus = small canal formed between adjacent hepatocytes

Transport proteins on apical/canalicular membrane transport various compounds into canaliculus (bile).

Canaliculi from adjacent cells interconnect like chicken-wire mesh and dumps into biliary tree at Canal of Hering, which connects to bile duct-->hepatic duct-->common hepatic duct-->duodenum via ampulla of Vater

Front 29

Bile:
Functions
Typical Solute Composition

Back 29

Eliminate endog/exog waste products (drugs, xenobiotics)

Excrete cholesterol

Promote digestion/absorption of lipids

Excretion of divalent heavy metals (Cu, Fe, Mn, Zn)

Composition:
70% bile acid
20% phospholipid
4% cholesterol
0.3% bilirubin

Front 30

Primary vs Secondary Bile Acids:
Site of Production
Examples
Conjugation

Back 30

Primary: formed in liver from cholesterol
Ex: cholic acid, chenodeoxycholic acid
Conjugated to bile salts (glycine, taurine, sulfate, glucoronate) before secretion!

Secondary: formed by intestinal bacteria
deoxycholic, lithocholic acid

Front 31

Cholic acid is a ____ bile acid and is converted to _______.

Back 31

Cholic acid = primary bile acid; converted to deoxycholic acid by bacteria (dehydroxylation); then conjugated to become bile salt

Front 32

Chenodeoxycholic acid is a _____ bile acid and is converted to ______.

Back 32

Chenodeoxycholic acid = primary bile acid; converted to lithocholic acid by bacteria (dehydroxylation); then conjugated to become bile salt

Front 33

Bile Acids:
Function

Back 33

Generate osmotic force to induce bile flow and secretion of bile lipids (phospholipids, cholesterol)

Essential for absorption of lipids and fat-soluble vitamins (A, D, E, K1)

Maintain cholesterol homeostasis--facilitates cholesterol absorption and elimination

Front 34

Bile-salt dependent vs Bile-salt independent bile flow:
General

Back 34

Bile-salt dependent:
Active, energy-dependent secretion of bile salts into canalicular lumen followed by passive movement of H2O/solutes

Bile-salt independent bile flow:
Driven by active secretion of other organic compounds (glutathione--aka GSH--and bicarb)

Front 35

Ductular secretion of bile:
Accompanied by?
Controlled by?

Back 35

Accompanied by water and bicarb
Under influence of secretin and VIP

Front 36

What hepatocyte transporters are located on the basolateral membrane?

Function?

Back 36

NTCP (sodium taurocholate cotransporting polypeptide): bile salt uptake

OATPs (organic anion transport proteins): organic anions for Na-idenpendent uptake of BS

Front 37

What hepatocyte transporters are located on the canalicular membrane?

Function?

Back 37

MDR's (multidrug resistance)

MDR1: excretion of organic cations, drug metabolites, toxins into bile

MDR3: excretion of phospholipids

MRP2 (multidrug resistance assoct prot 2): anion transport into bile (for BSIBF)

BSEP: bile salt export pump (stimulate BSDBF)

Front 38

This pump is important for BSIBF.

Back 38

MRP2 (multidrug resistance assocd prot 2)

Front 39

This pump is important for BSDBF.

Back 39

BSEP (bile salt export pump)

(bile salt independent = mlp2)

Front 40

____ of bile acids escape enterohepatic circulation and are eliminated in feces.

Back 40

Less than 10%!

Note: BA pool circulates 2-3 times per meal!

Front 41

Active absorption of bile acids occurs in the _____ via the ______.

Back 41

Absorption of bile acids restricted to terminal ileum via ASBT (apical Na+/bile salt transporter)

Front 42

ASBT:
Role
Effect of mutation

Back 42

Role = absorption of bile acids
Defect-->steatorrhea and fat-soluble vitamin malabsorption

Front 43

Liver:
Miscellaneous storage

Back 43

Stores vits A, D, B12
Stores Cu, Fe

Front 44

Back 44