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Pharm: 412 > Fatty acid synthesis, ketone bodies and cholesterol synthesis > Flashcards

Fatty acid synthesis, ketone bodies and cholesterol synthesis Flashcards

1
Q

Where does fatty acid synthesis take place?

A

The cytosol

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2
Q

In what state, high or low energy, does fatty acid synthesis take place?

A

It uses energy to construct the fatty acids during high energy states

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3
Q

What does insulin do in terms or up or down regulation of fatty acid synthesis?

A

It upregulates it and insulin initiation leads to weight gain

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4
Q

What is the first enzyme of of fatty acid synthesis?

A

Acetyl-CoA Carboxylase (ACC)

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5
Q

What is the role of Acetyl-CoA Carboxylase (ACC)?

A

Its the first enzyme and it used to convert acetyl-CoA into malonyl-CoA using bicarb

**it requires biotin (vit B7) as a prosthetic group

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6
Q

What are the allosteric regulation of ACC?

A

Citrate accumulation activates ACC (product from the TCA)

The end product of fatty acid synthesis palmitoyl-CoA inhibits ACC activation

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7
Q

What are the hormonal regulation of ACC?

A

Insulin activates ACC (leads to weight gain)

Glucagon and epi inhibits ACC activation

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8
Q

How are fatty acid synthesis and B-oxidation of fatty acid related?

A

They are inversely related - if one goes up the other will go down

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9
Q

What is the role of fatty acid synthase?

A

After malonyl-CoA production, its the enzyme that begins the cycle

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10
Q

What are the four steps that the fatty acid synthase follows?

A
  1. Condensation
  2. First reduction
  3. Dehydration
  4. Second Reduction
  • *different portions of the synthase handle these steps
  • ***goes thro 7 cycles until palmitic acid (C16:0) is formed
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11
Q

What does each cycle in the FA synthase utilizes?

A

They all use malonyl-CoA to add twoo carbon units to the elongating fatty acid

**The first step does not use malonyl-CoA

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12
Q

What is the role of the acyl carrier protein (ACP)?

A

It is required to carry and bind malonyl CoA to fatty acid synthase

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13
Q

What is the energy usage of the fatty acid synthesis?

A

1 ATP required for the synthesis of malonyl-CoA
***7 ATP are needed for the synthesis of 1 molecule of palmitic acid

Each cycle of FA synthase requires 2 NADPH
***14 NADPH are needed for the synthesis of 1 palmitic acid

***The energy of ATP and NADPH is stored in the fatty acids

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14
Q

Where does the acetyl-CoA come from and how does it relate to where fatty acid synthesis takes place?

A

The acetyl-CoA comes from the mitochondria but it needs a way to exit because fatty acid synthesis takes place in the cytoplasm

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15
Q

What is the citrate transport system?

A

Is used to transport acetyl-CoA into the cytoplasm

**only the carbon skeleton is transported and once in the cytosol it binds to free CoA to form acetyl-CoA. (reverse of the TCA)

***HIGH energy state is coupled to FA synthesis, glycolysis is the supplier of NADH in the cytosol

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16
Q

What is the overall balance of fatty acid catabolism vs synthesis maintained by?

A

Insulin:glucagon ration (IGR)

  • insulin turns sythesis on
  • *glucagon turns it off
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17
Q

What are the two enzymes that are key to the coordination of fatty acid metabolism?

A
  1. Acetyl-CoA carboxylase (ACC)
  2. Carnitine acyltransferase (CPT1) - this will limit transport of fatty acids into the mitochondrial matrix for B-oxidation
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18
Q

What happens when you take in a high carb meal and its effects on fatty acid metabolism?

A
  1. triggers release of insulin
  2. insulin activates ACC
  3. ACC catalyzes the formation of malonyl-CoA
  4. Malonyl-CoA inhibits CPT1, which stops CPT1 from bring fatty acids into the mitochondria (blocks B-oxidation)
  5. Insulin also block LpL (which cuts fatty acids off adipose) by blocking it there is inhibition of fatty acid release
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19
Q

What happens when blood glucose levels drop?

A
  1. Glucagon is released
  2. This inactivates ACC
  3. This leads to less malonyl-CoA
  4. Less malonyl-CoA removes the suppression of CPT1
  5. FAs enter the mitochondrial matrix and burn as fuel by B-oxidation
  6. Glucagon will also trigger release of fatty acids from adipose tissue by activating LpL
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20
Q

What happens when glucose levels are low or when someone cant utilize glucose (diabetes) ?

A

The acetyl-CoA can be converted to ketone bodies

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21
Q

Where does ketogenesis take place?

A

Acetyl-CoA is formed in the liver by B-oxidation of fatty acids and it can be converted into keytone bodies

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22
Q

What are the three types of keytone bodies?

A
  1. Acetone
  2. Acetoacetate
  3. D-B-Hydroxybutyrate (during unfed state (low glucose) or glucose intolerance (diabetes))
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23
Q

What gives off the sweet smell characteristic?

A

Acetone when produced in smaller quantities than the other ketones

24
Q

What is the purpose keytone bodies in the body?

A

Acetoacetate and B-hydroxybutyrate are transported thro blood to other tissues this is used by the brain since glucose is low and FAs cant be transported

**brain uses the keytone bodies during prolonged starvation

25
Q

What happens during diabetes when you have a high accumlation of ketones in the body?

A

When you cant use glucose it leads to keytones to accumulate in the body which leads to diabetic keto acidosis (DKA)
Acetoacetate and B-hydroxybutyrate are acidic

26
Q

Where do the reactions of keytone bodies take place?

A

In the mitochondrial matrix of the liver

27
Q

What is the role of HMG-CoA lyase in terms of regulation?

A

Its the key regulatory enzyme for ketogenesis

28
Q

What are the steps of ketogenesis

A

Happens in liver

  1. Two acetyl-CoA molecules are reacted to produce acetoacetyl-CoA
  2. Acetoacetyl-CoA reacts with another acetyl-CoA to produce HMG-CoA
  3. HMG-CoA breaks down acetoacetate and acetyl-CoA
  4. The acetoacetate can then be either decarboxylated to acetone or be reduced to B-hydroxybutyrate
29
Q

What is HMG-CoA synthase?

A

It catalyzes the production of acetoacetate from six-carbon compound HMG-coA

**takes acetoacetyl-CoA and combines an acetyl-CoA to it to create the HMG-CoA

30
Q

What does the HMG-CoA lyase do?

A

It removes an acetyl-CoA from HMG-CoA to produce Acetoacetate (which then leads to acetone and d-B-hydroxybutyrate)

31
Q

What does insulin do to HMG-CoA synthase?

A

It inhibits it

32
Q

What does glucagon do to HMG-CoA lyase?

A

It activates it

33
Q

What are the ketone bodies as fuel?

A
  1. Acetone is a dead end product and leads to a fruity smell
  2. Acetoacetate and B-hydroxybutyrate can be interconverted and used as energy fuel in other organs, like the brain and muscle

***RBC can not use this!!!!

34
Q

What does ketone bodies catabolims lead to which can be used to create ATP?

A

It breaks down to acetyl-CoA, which normally will enter the TCA cycle

35
Q

What s ketosis?

A

When the body is in an enhanced state of ketogenesis

  1. normally not harmful - happens during starvation to feed brain mainly
  2. every cell type can use this expect the RBC! (this is because RBC doesnt have mitochondria so it doesnt have TCA
  3. It can be fatal due to leading to ketoacidosis
36
Q

Where does most of the cholesterol in the body come from?

A

Most majority does not come from foods like eggs and meat but its produced by the liver, which can make cholesterol out of anything we eat

37
Q

What is the bad part about cholesterol?

A

Its the lipoproteins, or cholesterol carriers.
These are low density lipoprotein (LDL) = bad
High density lipoprotein (HDL) = good

38
Q

How much cholesterol is produced in the liver and how much comes from diet?

A

The liver produces around 800 mg per and about 200 mg comes from diet
**if you eat 600 mg of cholesterol in diet only 200 mg will be absorbed

***if someone doesnt eat any cholesterol (vegan) the liver will compensate to keep the 1000mg goal

39
Q

What is half of the cholesterol in the body used to produce?

A

Its for bile acid synthesis

40
Q

Where do 90% of the bile salts which are reabsorbed happen at?

A

In the distal ilium and transported back to the liver

41
Q

Why does something high in fiber help to prevent cholesterol?

A

It blocks re-absorption into the body which allows us to pass it and lower cholesterol

42
Q

What are the physiologically significant functions of biles?

A
  1. Synthesis of biles and excretion in the feces represent the only significant mech for elimination of excess cholesterol
  2. they facilitate digestion of dietary triacyleglycerols by acting as emulsifying (soap) agents that render fats accessible to pancreatic lipases
  3. Facilitate the intestinal absorption of fat-soluble vitamins
43
Q

How does excess LDL in blood cause atherosclerotic plaque?

A
  1. Liver produces major load of cholesterol to meet need of tissue, it loads this cholesterol into LDL to travel the aqueous environment of blood
  2. After they distribute the cholesterol the unused LDLs come back to the liver for recycling
  3. LDL levels inc in blood when the livers ability to re-absorb LDL is impaired
  4. These un-reabsorbed LDL take shelter under internal cell layer of veins and arteries
44
Q

What is the precursor of all cholesterol synthesis?

A

Acetate (as acetyl CoA)

45
Q

Where does production of cholesterol take place?

A

Happens in the cytosol and the liver is the primary site of production

46
Q

What happens during stage one of the cholesterol synthesis?

A

The condensation of three acetate units to form the six-carbon intermediate mevalonate

47
Q

What happens during stage two of cholesterol synthesis?

A

Conversion of mevalonate to activated isoprene units

**this uses three ATPs to activate carbons

48
Q

What happens during stage three of cholesterol synthesis?

A

Polymerization of six 5-carbon isoprene units to form squalene

49
Q

What happens during stage four of cholesterol synthesis?

A

Cyclization of squalene to form the four rings of the steroid nucleus

50
Q

What is the most cholesterol-rich organ of the body and why is?

A

Its the brain. the reason is the LDLs can not cross the blood brain barrier so the brain must do all its cholesterol synthesis on its own

51
Q

What is the role of HMG-CoA reductase in the terms of regulation of cholesterol?

A

Its the rate limiting step in cholesterol synthesis and is the most regulated step in cholesterol synthesis

52
Q

What is the transcriptional control of HMG-CoA reductase?

A
  1. Synthesis of HMG-CoA mRNA is controlled by one of the family of sterol regulatory element binding proteins (SREBPs), these transcription factors directly activate the expression of more than 30 genes, which control all cofactors required for cholesterol synthesis
  2. When enough cholesterol is present, the cell stops making HMG-CoA reductase mRNA and the level of the enzymes falls
53
Q

How is the regulation of the rate of enzyme degradation lead to cholesterol synthesis stopping?

A
  1. rising lvls of cholesterol stimulates HMG-CoA reductase to be proteolytically degraded
  2. HMG-CoA reductase senses the higher levels of cholesterol leading to shape change
  3. This becomes ubiquintinated and then degraded by the proteasome
54
Q

How is cholesterol synthesis regulated by covalent modification?

A
  1. HMG-CoA exists in phosphorylatled (inactive) and unphosphorylated (active) forms
  2. Glucagon and Epi inactivates HMG-CoA reductase thro phosphorylation which inhibits cholesterol synthesis
  3. Insulin activates HMG-CoA reductase thro dephosphorylation, which promotes cholesterol synthesis
55
Q

How is regulation of excess intracellular free cholesterol done?

A

Thro acyl-CoA: cholesterol acyltransferase, ACAT

**it adds a fatty acid which makes cholesterol ester, which is transported by lipoprotein paricle known as VLDL to other tissues that use cholesterol

Pharm: 412 (4 decks)

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