Lecture 47 & 48: Hepatic Metabolism I

Question 1

What % of body weight is the liver?

Answer 1

~2%

Question 2

What are the two zones of hepatic parenchymal cells (hepatocytes)?

What are the functions of each?

Answer 2

Periportal and perivenous

periportal:

• cholesterol synth
• bile formation
• oxid of FAs
• amino acid catabolism
• urea synthesis
• gluconeogenesis

perivenous

• gluc—>glycogen & FAs
• glycolysis
• ketogenesis
• detox

Question 3

What are some options for liver replacement?

Answer 3

• full liver transplant
• partial transplant
• artificial liver
• portal cell recolonization (stem cell/pt’s own cells/donor cell?)

Question 4

What regulatory roles does insulin play on the liver?

Answer 4

inhibits: gluconogenesis, lipolysis, prot degrad

Promotes: glycogen synthesis, lipogenesis, prot synth

Insulin does NOT ∆ the flux of glucose in or out of the hepatocyte

Question 5

is the regulation on hepatic glycogen synthesis?

Answer 5

pro: glucagon
anti: insulin

Question 6

Why isn’t glucose flux in the liver insulin-dependent?

Answer 6

b/c hepatocytes use GLUT-2 and GLUT-3 transporters which:

a) do not require insulin to be translocated to the plasma membrane
b) are expressed constitutively

Question 7

Which glucose kinase-ing enzyme is predominant in the hepatocyte?

Answer 7

glucokinase phosphorylates ~80% of incoming gluc molecules (vs. hexokinase which P’s about 20%)

glucokinase has a higher K_m than hexokinase (requires a higher substrate concentration to reach V_max)

“Therefore transport depends on phosphorylation” Why?

REALLY FUZZY ON THIS POINT SEE SLIDE #15

Question 8

Compare and contrast glycogen storage in SKM vs. liver?

Answer 8

AMOUNT

Individual cell level: hepatocytes can hold much more glycogen/cell (50g vs. 12.7g)

But since there’s so much more SKM, overall it holds more

FUNCTION

SKM cells lack G6Pase enzyme, therefore it can only breakdown glycogen for use within that same cell vs.

liver (and kidney, though it doesn’t store nearly as much) has G-6-Pase and can therefore release glucose into the circulation.

Question 9

What regulates glycogen breakdown in SKM vs. liver?

Answer 9

Each has its own isozyme.

SKM: in SKM, AMP stimulates the unphosphorylated glycogen phosphorylase

Liver: in hepatocytes, glucose inhibits the phosphorylated glycogen phosphorylase

Question 10

How is fructose metabolized? Where along the pathway is the most serious deficit and why?

Answer 10

Minority: fructose—hexokinase—>F-6-P—>CAC

Majority: fructose—fructokinase—>F-1-P—>aldolase—>etc.

Mutation in the aldolase is most serious b/c of build-up of F-1-P (P_i sequestration?)

Question 11

When does liver switch from storing glucose as glycogen to storing glucose in FAs?

Answer 11

Once all the branches of the glycogen are completely full

Question 12

What gluconeogeneic pathway is increased by anaerobic respiration?

Answer 12

Cori cycle: lactic acid—SKM-blood-liver—>glucose

normally resp. for ca. 15% of liver glucose production

Question 13

Tell me about gluconeogenesis from amino acids?

Answer 13

• normally accounts for ca. 10% of liver glucose production
• incr vastly by high protein diets and starvation
  
  • in which case ~50% from alanine

Question 14

What condition results when liver nitrogen metabolism fails?

Why is this a problem?

Answer 14

hyperammonemia

NH3 is particularly toxic to the brain

Question 15

When is urea synthesis increased?

Answer 15

increased a.a. delivery to the liver (e.g. after a protein-rich meal, muscle autophagy in starvation)

Question 16

What processes of nitrogen metabolism occur in the liver?

Answer 16

1. urea synth
2. excess a.a. catabolism
3. generation of glucose from Alanine-Glucose shuttle
4. non-essential a.a. synth
5. hypoxanthine—>xanthine—>uric acid
6. amino acid sync (stores and responds to levels of free a.a.’s)

Question 17

What can the liver use to make new glucose?

Answer 17

1. lactate
2. glycerol
3. amino acids

Question 18

How does EtOH interact with the gluconeogenic pathway?

Answer 18

Both EtOH catabolism and gluconeogenesis require NAD⁺, so EtOH consumption can out-compete the gluconeogenic pathway’s need for NAD⁺ at high concentrations leaving the individual susceptible to hypoglycemia.

• NAD⁺ needed at:
  
  • lactic acid—>pyruvate
  • malate—>oxaloacetate

Question 19

How is gluconeogenesis regulated? (Main step of control?)

Answer 19

Main step of regulation in both glycolysis and gluconeogenesis is at PFK II

High [cAMP] inhibits PFK II and pyruvate kinase

insulin promotes it

glucagon inhibits it

Question 20

What negative consequences can occur when one takes in too much fructose PO? How about IV?

Answer 20

PO: fructose is poorly absorbed in the intestines (by GLUT5 transporter); amounts >50g can lead to diarrhea (b/c fructose then acts as an effective osmole?)

IV: excess fructose can cause build up of F-1-P (fructose is rapidly taken up by hepatocytes and fructokinase “traps” it in more rapidly than F-1-P aldolase can break it down)

• F-1-P is toxic at high conc

Question 21

Describe hepatic glucose metabolism in the post-absorbtive state?

Answer 21

Question 22

Describe hepatic glucose metabolism after a CH₂O-rich meal?

Answer 22

Question 23

Describe hepatic glucose metabolism after a carnivorous meal?

Answer 23

Question 24

Where does the liver get the majority of the energy it needs?

Answer 24

FA oxidation

Question 25

What aspects of lipid metabolism occur in the liver?

Answer 25

1. FA oxidation
2. Ketogenesis (can’t use them, though)
3. lipogenesis
4. desaturation of FAs
5. synth of VLDL and chylomicron remnants
6. de novo choline synth and choline catabolism
7. de novo cholesterol synth
8. Cholesterol elimination

Question 26

What is the hormonal regulation of ketogenesis?

Answer 26

insulin decreases ketogen

glucagon increases it