Wk5 Liver Metabolism

Question 1

What is the liver doing with nutrients in the fed state:

Answer 1

excess protein/carbs –> blood proteins, glucose, VLDL

Question 2

What gets added to xenobiotics/waste metabolites in Phase I detoxification reactions:

Answer 2

-OH

gets hydroxylated

Question 3

What happens in Phase II of detox reaction:

Answer 3

addition of sulfate, methyl groups, glutathione, or glucuronate to the hydroxyl group to form secondary metabolite suitable for excretion.

Question 4

Important Phase I metabolizing enzymes:

Answer 4

cyt P450 family

**all use NADPH

**all use O2

Question 5

Detoxifying molecule that gets used up by EtOH:

Answer 5

Glutathione

Question 6

Early sx of Acetaminophen toxicity:

Answer 6

N/V shortly after ingestion

Question 7

Most common cause of acute liver failure:

Answer 7

Acetaminophen toxicity

Question 8

Sx 24-48 after acetaminophen OD:

Answer 8

Aminotransferase levels increase

Lactate dehydrogenase increases

Prothrombin time increases

Question 9

Sx 72-96 hours after acetaminophen OD:

Answer 9

Jaundice

Hepatomegaly

Bilirubin increases

Encephalopathy/coma

Hypotension

Hypoglycemia; metabolic acidosis

Death by general organ failure

Question 10

NAPQI

Answer 10

cytotoxic product of acetaminophen conversion by:

CYP2E1

**EtOH induces expression and increases rate

Question 11

Tx for acetaminophen toxicity?

Answer 11

cimetidine

**out-competes for CYP2E1 binding

-also an H2 blocker

Question 12

CYP2E1 role in EtOH metabolism:

Answer 12

MEOS pathway –> acetaldehyde

Question 13

Mech of EtOH liver damage:

Answer 13

Acetaldehyde –> Kupffer cells –> TGF-B, ROS, NO “respiratory burst” –> Stellate cell stimulation –> fibrosis

Question 14

Liver and glucose relationship in fed state:

Answer 14

insulin + glucose –> liver –> TG’s, Glycogen, glycolysis

Question 15

Liver and glucose relationship in fasted state:

Answer 15

Glucagon & Epi –> liver –> glycogen degradation + gluconeogenesis –> glucose

Question 16

Two important intermediates between glycogen and glucose:

Answer 16

Glycogen –> Glucose 1-phosphate Glucose 6-phosphate –> (Gluc-6-phosphatASE) –> glucose

**gluconeogenesis joins at G6P step as well

Question 17

Enzyme that interconverts G-1-P and G-6-P:

Answer 17

PGM1 – phosphoglucomutase

Question 18

Path from dietary carbs and FAs to bile salts:

Answer 18

–> acetyl CoA –> cholesterol –> bile salts

**5% production needed – 95% get recycled

Question 19

Fate of excess dietary carbs:

Answer 19

FAs –> TGs –> VLDL

Question 20

Source of two N’s needed for Urea synth:

Answer 20

Aspartate

free ammonia

Question 21

Form of excess Nitrogen transport in the blood after protein degradation in tissues:

Answer 21

Glutamine

**review slide 30

Question 22

a-KG + NH4 –> glutamate + NH4 –> glutamine

location of this reaction?

Answer 22

muscle

peripheral tissue

Question 23

Glutamine - NH4 –> glutamate - NH4 –> a-KG

location of this reaction?

where does the free ammonia go?

Answer 23

Liver

urea cycle –> urine

Question 24

Path of ketone body synthesis in liver:

Answer 24

FA’s –> Acetyl CoA –> Acetoacetate/B-hydroxybuterate –> ketone bodies (blood) –> muscle (uses acetoacetate for energy in extended fasting/starvation)

Question 25

Excess NH4 left over after periportal cells is handled how in perivenous cells if CPS-I has been overworked?

Answer 25

Perivenous cells express glutamine synthase to make NH4 back into glutamine for another go round.

**slides 31-32

Question 26

Creates a “safe zone” for free ammonia between the periportal cells and pervenous cells

keeps free ammonia out of circulation

Answer 26

Wnt

High expression in perivenous zone causes increased expression of glutamine synthase to convert NH4 back to glutamine before heading out into circulation

Question 27

Maintaining blood glucose during fasting is dependent on?

Answer 27

urea cycle

Question 28

Two important role of pentose phosphate pathway:

Answer 28

1. production of NADPH

2. Ribose for nucleotide sunthesis

Question 29

3 important roles of NADPH from pentose phosphate pathway:

Answer 29

1. FA synthesis
2. glutathione reduction (detox)
3. Cyp450 reactions

Question 30

Importance of glycosylation of blood proteins?

Answer 30

increases survival in blood

Question 31

O-linked glycoproteins

Answer 31

Serine

Question 32

N-linked glycoproteins

Answer 32

Asparagine

Question 33

Location of glycolsylation initiation

Answer 33

lumen of ruough ER

Question 34

Glycosylation modification and transfer to target pprotein happens where?

Answer 34

rough ER

Question 35

Modification og glycoproteins before exocytosis happens where?

Answer 35

Golgi

Question 36

Aside from glycogen storage, what is PMG1 important for?

Answer 36

glycosylation

Question 37

increased conjugated + unconjugated bilirubin:

Answer 37

liver damage

Question 38

increased unconjugated bilirubin only:

Answer 38

hemolysis

Question 39

serum ammonia?

Answer 39

urea cycle probs

Question 40

rate limiting step in bilirubin elimination?

Answer 40

transport across canilicular membrane

**not glucouronidation

Question 41

AST:ALT = 1

Answer 41

acute hepatocellular disorder

Question 42

AST:ALT >/= 2

Answer 42

EtOH abuse

Question 43

Enzyme more specific for liver damage:

Answer 43

ALT&raquo_space;> AST

Question 44

alk phos location

Answer 44

canilicular membrane of hepatocytes

Question 45

5’ nucleotidase location

Answer 45

canilicular membrane of hepatocytes

Question 46

gamma-glutamyltranspeptidase location?

Answer 46

bile duct epithelial cells

Question 47

protein with long half life

not good for detecting acute live damage

good for assessing malnutrition

Answer 47

serum albumin

Question 48

Increased IgA

Answer 48

EtOH liver disease

Question 49

Increased IgG

Answer 49

autoimmune hepatitis

Question 50

increased IgM

Answer 50

primary biliary cirrhosis