Liver Metabolism 4: Lipid Metabolism #2

Question 1

What si the building block molecule to synthesis FAs?

Answer 1

Acetyl CoA from citrate from the TCA cycle

Question 2

What tissues can synthesize FAs de novo?

Answer 2

Hepatocytes (vast majority of it >80%)

Mammillary glands

Adipose tissues

Question 3

Where in the mitochondria does FA synthesis in hepatocytes occur?

Answer 3

Cytosol

Question 4

How does acetyl CoA produced in the mitochondria allowed to be transported across the cytosol?

Answer 4

1) Oxaloacetate + Acetyl CoA -> citrate
- uses citrate synthase as enzyme

2) citrate is able to cross mitochondria membrane and is then lysed into OAA+ acetyl CoA again in the cytosol
- uses ATP citrate lyase as enzyme

Question 5

When do high levels of citrate present in hepatocytes?

Answer 5

In high energy concentration
- high levels of ATP and NADH and low levels of ADP

in high energy concentrations, turns off isocitrate enzymes in TCA and causes citrate to build up in mitochondria. Citrate build up = FA synthesis

Question 6

What is the relationship between citrate and acetyl CoA carboxylase enzyme?

Answer 6

acetyl CoA carboxylase enzyme is topically inactive in the cytosol UNLESS high levels of CITRATE are present.
- in which case that are activated and acetyl CoA in cytoplasm is converted into malonyl CoA

Question 7

What does malonyl-CoA help regulate?

Answer 7

Its presence in the cytosol inhibits CPT 1 and 2 receptors required for LCFA degradation

there is no point in degrading and synthesis of FAs at the same time

Question 8

What are the 4 broad steps of FA synthesis?

Answer 8

1) condensation
2) reduction #1
3) dehydration
4) reduction #2

Question 9

How does palmitoyl CoA cause feedback inhibition?

Answer 9

It’s presence in the cytosol turns off acetyl CoA carboxylase enzymes

Question 10

How does insulin affect FA synthesis?

Answer 10

Activates acetyl CoA carboxylase regardless of current feedback present
- override command

Question 11

How does AMP-activated protein protein kinase affect FA synthesis?

Answer 11

Is a protein kinase that is only activated in the presence of AMP
- low energy levels only

When activated, allosterically inhibits Acetyl-CoA carboxylase enzymes regardless of current conditions in cytosol
- override command

Question 12

Why does lipid synthesis occur when large carbohydrate meals are consumed?

Answer 12

Because in hepatocytes only, the synthesis of TAGs and FAs can be done via glucose/carbohydrate molecules
- “cross-talk”

Question 13

What is the reducing equivalent Molecule used in FA synthesis?

Answer 13

NADPH

Is produced in the Pentose pathway shunt and conversion of OAA to malate

the conservation of OAA to malate and malate to pyruvate via malic enzyme is ONLY found in hepatocytes

Question 14

Hepatic steatosis

“Fatty liver disease (also NAFLD)

Answer 14

Overaccumulation of lipid droplets on the liver usually due to deficency in MTTP or over consumption of fats

Causes:

• too much TAG synthesis and exceeds ability of liver to produce VLDL molecules
• aging
• alcoholism
• some drugs
• obesity
• sedentary lifestyle

chronically leads to steatohepatitis (fatty liver with fibrosis) and activates stellate (ITO cells) to produce more fibrosis and eventually cirrhosis/end liver disease

is reversible UNTIL steatohepatitis is reached

hepatic steatosis is a risk factor for diabetes/atherosclerosis/cardiovascular diseases

Question 15

Why cant liver use ketone bodies for fuel?

Answer 15

Liver doesnt have thiophorase enzymes

Question 16

What is the rate limiting enzyme in ketogenesis?

Answer 16

HMG-CoA synthase

Question 17

What is the rate limiting enzyme for FA synthesis

Answer 17

Acetyl CoA carboxylase

Question 18

How is cholesterol and acetone produced differently, but with the same rate limiting enzyme and similar steps to cholesterol synthesis?

Answer 18

Cholesterol = is done inside the cytosol

Acetone = is done inside the mitochondria

Question 19

What are the ketone bodies produced in ketogenesis?

Answer 19

Acetoacetate and B-hydroxybutryate

*these are both the two physiological ketone bodies that can be used for energy

acetoacetate spontaneously degrade EPO acetone which is not physiological ketone body

Question 20

Diabetic ketoacidosis

Answer 20

In untreated diabetes (especially type 1)

Causes increased ketone body production and leads to damage to biological processes**

Question 21

What are the major factors for FA synthesis and degradation?

Answer 21

Synthesis = after carb heavy meal and high insulin levels

Degradation = in starvation and low insulin levels

Question 22

What is the common presentation with all Fatty acid oxidation disorders

Answer 22

Hypoketosis
- very low levels of acetyl CoA since cant use Fatty acids as fuel

Hypoglycemia
- can only use glucose as fuel