Liver Biochemistry

Question 1

Portal Vein

Answer 1

Nutrient rich blood

Question 2

Hepatic Artery

Answer 2

Oxygen rich blood

Question 3

Sinusoids

Answer 3

fenestrated to allow oxygen and nutrients through

Question 4

Hepatocyte

Answer 4

workhorse of the liver –> every hepatocyte can do ALL the functions of the liver

Question 5

Hepatic Stellate Cells

Answer 5

storage sites of lipids and Vitamin A

- when activated –> lose Vitamin A stores and deposit collage in space of Disse

Question 6

Hepatic Pit Cells

Answer 6

liver associated lymphocytes

- NK Cells protect against viruses and tumor cells

Question 7

Hepatic Endothelial Cells

Answer 7

“leaky” –> fenestrated with no basement membrane

Question 8

Kupffer Cells

Answer 8

endocytic, phagocytic macrophages

• protect against bacteria
• source of inflammatory mediators that contribute to liver injury

Question 9

Flow through liver

Answer 9

enter through the blood –> leave through hepatic vein

- leave through bile duct too

Question 10

Receiving and processing nutrients

Answer 10

liver converts excess protein and carbs to blood proteins, glucose, and VLDL
- AA and other monosaccharides enter liver and are processed to VLDL, glucose, and proteins

Question 11

Detoxifying xenobiotics & metabolites

Answer 11

liver is the first place ingested things go –> has low pressure, high surface area –> serves as a sieve to neutralize toxin

Question 12

Phase Reactions

Answer 12

Phase I –> add hydroxyl groups to substrates
Phase II –> add sulfate, methyl, glutathione, or glucoronate to hydroxyl groups (increases solubility and makes them easier to secrete)

Question 13

Cytochromes

Answer 13

Phase reactions are accomplished by the reducing power of:

1. NADPH
2. FAD & FMN
3. Fe-heme & O2
   - with multiple drugs –> cytochrome will metabolize drug it has highest affinity for first

Question 14

Glutathione

Answer 14

Reduced glutathione (GSH)

• glutamic acid, cysteine, glycine
• ethanol metabolism depletes hepatic GSH

Question 15

Vinyl Chloride

Answer 15

Phase I –> CYP2E1 to chloroethylene oxide (can damage the liver and lead to angiosarcoma)
Phase II –> chloroacetaldehyde -(glutathione transferase)-> conujugation and excretion

Question 16

Acetaminophen

Answer 16

Most common cause of acute liver failure
Early –> N/V shortly after ingestion
24-48 Hrs -> elevated aminotransferase, lactate dehydrogenase, PTT
72-96 Hrs -> jaundice, hepatomegaly, bilirubin, encephalopathy, hypotension

Question 17

Indication of Acetaminophen toxicity?

Answer 17

Serum [ ] of acetaminophen after ingestion predicts severity of poisoning (NEED TO KNOW WHEN IT WAS INGESTED)

Question 18

Acetaminophen metabolism

Answer 18

• before Phase I –> UDP-glucuronyl transferase or sulfo transferase turn acetaminophen into form that can be excreted
• CYP2E1 -> convert Acetaminophen into NAPQI (toxic to liver) –> increased with ethanol
• NAPQI –> can be converted to excretable form by GSH

Question 19

Ethanol metabolism

Answer 19

NEEDS NADPH

• uses MEOS (microsomal ethanol oxidizing system)
• ethanol is metabolized to Acetaldehyde

Question 20

Acetaldehyde

Answer 20

• responsible for long term damage to liver associated with ethanol consumption
• taken up by Kupffer cell –> become activated Kupffer cell –> activates Stellate cell using TGF-beta and ROS/NO
• stimulated Stellate cell deposits collagen and induces fibrosis

Question 21

Liver (fed state)

Answer 21

insulin induces TAG synthesis, glycogen synthesis, and activate glycolysis

Question 22

Liver (fasted state)

Answer 22

Glucagon and Epi induce glycogen degradation, gluconeogensis

Question 23

Liver (glycogen and glucose balance)

Answer 23

Phosphoglucomutase (PGM1) interconverts G-1-P and G-6-P (both forward and reverse reactions)
Glycogen -> G-1-P G-6-P -> Glucose

Question 24

Bile Acids and cholesterol

Answer 24

Cholesterol synthesized in liver are used for bile salts, cell membranes, store fatty acids, and steroid hormones

Question 25

Excess carbohydrates

Answer 25

converted to FAs in liver --> VLDL --> bind to LPL --> FA and glycerol --> recycled as IDL or LDL

Question 26

Excess nitrogen

Answer 26

results from AA catabolism --> must be excreted as urea - Aspartate (intracellular N buffer) and ammonia are direct N donors in liver - Glutamine is blood buffer of N --> main source of N from body that enters liver

Question 27

Muscle and peripheral tissues conversion to glutamine

Answer 27

alpha-ketoglutarate --(NADPH w/ GDH)-> Glutamate --(ATP w/ glutamine synthetase)-> Glutamine

Question 28

Liver conversion of glutamine

Answer 28

Glutamine --(Glutaminase)-> Glutamate --(GDH)-> alpha-ketoglutarate

Question 29

Liver lobule organization

Answer 29

Periportal (periphery) | Perivenous (near central vein)

Question 30

Enzymes?

Answer 30

- Glutaminase is located periportally --> converts glutamine to glutamate and creates free ammonia - CPSI converts free ammonia to Carbamoyl phosphate - Glutamine Synthase takes extra free ammonia and recreates glutamine if too much ammonia present for CPSI

Question 31

Glutamine synthase

Answer 31

expression is restricted to perivenal hepatocytes which are regulated by beta-catenin - Wnt increases in [ ] as you approach central vein --> creates 'safe zone' for free ammonia to be substrate for urea cycle without releasing it into circulation

Question 32

Ketone bodies

Answer 32

synthesized from FA beta-oxidation during fasting/starvation | - serve as alternative fuel source to reserve glucose for tissues that are dependent on it

Question 33

Pentose Phosphate Pathway

Answer 33

- liver has high requirement of PPP - NADPH is created during PPP --> used for biosynthetic and detox reactions - PPP also creates 5-carbon ribose sugars that are used for nucleotide synthesis

Question 34

Glycoproteins

Answer 34

the liver makes A LOT of proteins --> many of them become glycosylated to be protected from degradation - they become glycosylated in lumen of ER beginning with dolichol --> each glycosylation occurs because of nucleotide conjugates - glycosyl chain is then transferred to its specific protein

Question 35

Phosphoglucomutase 1

Answer 35

PGM1 --> important for interconverting glucose-1-phosphate to glucose-6-phosphate - also important in generating UDP-galactose which is a glycosylation intermediate - mutations in PGM1 = defects in glycosylation

Question 36

Dietary supplementation with galactose in mutated PGM1?

Answer 36

increased amounts of properly glycosylated transferrin - improved symptoms including inducing puberty - LH is a glycoprotein that became functional for those individuals who had defects in glycosylation

Question 37

Bilirubin metabolism

Answer 37

IN LIVER --> bilirubin is glycosylated to bilirubin diglucuronide by glucoronosyl transferase - the diglucuronide form is more soluble and excreted in urine and bile