Fatty Acid Oxidation And Ketogenesis

Question 1

Too many fatty acids in blood stream

Answer 1

Can be dangerous

So liver oxidizes them into acetyl CoA

Question 2

From acetyl CoA —>

Answer 2

Make ketone bodies

Question 3

Ketone bodies are only produced when

Answer 3

1. Low insulin

2. A lot of fatty aid oxidation is going on

Question 4

When

Answer 4

1. Overnight fast
2. Endurance exercise
3. Stress (epi)
4. Low carb diets (alternative fuel)

Question 5

What triggers breakdown of TG and release of FA from adipose tissue?

Answer 5

Glucagon or epinephrine

Question 6

Triacylglycerol —> glycerol + 3 fatty acids

Requires?

Answer 6

3 different lipases- each cut off one fatty acid

Question 7

3 lipases required

Answer 7

1. ATGL
2. HS lipase
3. MAG lipase

Question 8

Process of cleaving off 3 fatty acids

Answer 8

In glucagon/epi signaling cascade cAMP activates PKA —> PKA phosphorylates perilipin to activate it —> perilipin restructures lipid droplet to make TG accessible —> perilipin also interacts with ATGL which cleaves off first FA (TAG —> DAG) —> PKA also activates HS lipase by phosphorylating it —> HS lipase cleaves off second FA (DAG —> MAG) —> MAP lipase cleaves off third fatty acid (MAG —> glycerol + 3 FA)

Question 9

Long chain fatty acids

Answer 9

• Hydrophobic

- Can be toxic at high concentrations because hydrophobic interactions in proteins are disrupted

Question 10

How are fatty acids transported to tissues?

Answer 10

Albumin

Question 11

Albumin

Answer 11

• Can bind multiple FA b/c has hydrophobic pocket

- Delivers FA to lipid transfer protein at plasma membrane which brings FA into cell

Question 12

Fatty acids must be degraded by removal of

Answer 12

2-C units

Question 13

Fatty acid oxidation occurs in

Answer 13

Mitochondrira

• FA are transported in by lipid transfer protein after albumin delivers them

Question 14

2-C unit is released as ________

Answer 14

Acetyl-CoA

NOT free acetate

Question 15

Activation step of FA oxidation

Answer 15

• Only needs to happen once

Requires CoA (SH group) and ATP (make thioester bond)

Question 16

Activation Step

Where?
Driven by?

Answer 16

Free fatty acid + HS-CoA + ATP —> Acyl-CoA + AMP + PPi

• Occurs at OMM
• Driven by hydrolysis of PPi

Question 17

Activated fatty acids can?

Answer 17

Cross the OMM

Question 18

Why have to add a CoA to free fatty acid?

Answer 18

Need to attach a carnitine molecule to the FA so that it can be transported across the IMM

Question 19

Transport across IMM

Answer 19

Acyl-CoA + carnitine acyl-carnitine + HS-CoA

Enzyme: carnitine acyltransferase I

Attach carnitine to Activated FA —> CoA comes off and releases energy because break thioester bond

Question 20

_______ carries acyl carnitine across IMM into matrix

Answer 20

Translocase

Question 21

Carnitine acyltransferase II

Answer 21

Add CoA back to FA in the matrix —> acyl- CoA

Question 22

What happens to carnitine after add CoA in matrix?

Answer 22

Recycle carnitine back out via translocase for use again

Question 23

Beta-Oxidation Total Reaction

Answer 23

Palmitoyl CoA (16-C) + 7 FAD + 7 NAD+ + 7 H2O + 7 CoA —>

8 acetyl CoA + 7 FADH2 + 7 NADH + 7 H+

Question 24

Summary of mechanism chemistry

Answer 24

Single bond —> double bond —> alcohol —> ketone

Question 25

Step 1

Answer 25

Convert single bond between alpha and beta carbons to a double bond - Oxidation / reduction C-C oxidized to C=C FAD is reduced to FADH2 —> 1.5 ATP

Question 26

Step 2

Answer 26

Add water molecule to double bond —> double bond becomes an alcohol

Question 27

Step 3

Answer 27

Convert alcohol into a ketone -OH —> C=O NAD+ reduced to NADH —> 2.5 ATP

Question 28

Step 4

Answer 28

Acetyl CoA is split off and attach CoA to beta carbon of chain that has now been shortened by 2 carbons Acetyl CoA goes through TCA cycle C=(n-2) goes back and cycle is repeated 7 time

Question 29

Get ____ ATP per cycle

Answer 29

14

Question 30

Complete oxidation of 1 palmitic acid yields

Answer 30

108 total ATP 106 net ATP (2 used in activation step)

Question 31

Large energy yield is due to

Answer 31

Highly reduced state of carbon in fatty acids

Question 32

Complete oxidation of one glucose yields

Answer 32

80 ATP

Question 33

Regulation of fatty acid oxidation is linked to

Answer 33

ETC and how rapidly NAD+ and FAD can be regenerated

Question 34

Carnitine acyltransferase I regulation Result:

Answer 34

Negative allosteric modifier: Malonyl CoA (made by acetyl CoA carboxylase in fed state) Result: FA do not get into mitochondria in fed state

Question 35

____ control rate of O2 consumption (rate of ETC)

Answer 35

ADP ``` High ADP = speed up ETC Low ADP (high ATP) = slow down ETC ```

Question 36

Because ATP is utilized in gluconeogenesis...

Answer 36

ADP levels rise —> ETC speeds up —> FAD and NAD+ regenerated —> fatty acid oxidation increases

Question 37

NADH and FADH2

Answer 37

Negative allosteric modifiers

Question 38

Ketogenesis occurs in

Answer 38

Liver

Question 39

What happens during ketogenesis

Answer 39

Ketone bodies are synthesized from acetyl CoA —> generating an alternative fuel source to glucose

Question 40

Advantages of ketone bodies (2)

Answer 40

1. Water soluble | 2. Reduces burden on liver to continue gluconeogenesis at a high rate

Question 41

Every tissue except ____________ can use FA for energy

Answer 41

RBC and brain

Question 42

Liver ________ ketone bodies but cannot ________

Answer 42

Liver synthesizes ketone bodies but cannot oxidize them because lack CoA transferase

Question 43

Step 1 ketogenesis

Answer 43

Condense 2 acetyl CoA together —> acetoacetyl CoA + CoA

Question 44

Step 2 ketogenesis

Answer 44

Acetoacetyl CoA + acetyl CoA + H2O —> HMG-CoA + CoA If have insulin...HMG-CoA used by HMG-CoA reductase to make metholonate If have no insulin...

Question 45

Step 3 ketogenesis

Answer 45

HMG-CoA —> Acetoacetate + CoA

Question 46

Step 4 ketogenesis

Answer 46

Depending on NAD+/NADH ... Form D-3-hydroxybutyrate or acetone

Question 47

3 ketone bodies Which predominates?

Answer 47

- Acetoacetate - Acetone - D-3-hydroxybutryrate (predominates)

Question 48

Ketone bodies do not rise significantly in blood until

Answer 48

2-3 days of starvation

Question 49

Advantage of ketone bodies

Answer 49

Glucose and muscle sparing Reduces burden on liver for gluconeogenesis —> don’t have to breakdown as much muscle protein

Question 50

Conditions that increase KB synthesis and oxidation

Answer 50

1. Length of fasting (>3 days) 2. Low carb diets 3. Untreated type 1 diabetes 4. Chronic alcoholism

Question 51

Untreated Type 1 diabetes vs. Type 2 diabetes

Answer 51

Untreated type 1 diabetes leads to diabetic ketoacidosis Type 2 diabetics do not show ketoacidosis

Question 52

Chronic alcoholism leads to

Answer 52

Alcohol induced ketoacidosis

Question 53

Oxidation of KB- step 1

Answer 53

D-3-hydroxybutyrate + NAD+ —> Acetoacetate + NADH + H+

Question 54

Oxidation of KB- step 2

Answer 54

Acetoacetate + succinyl CoA —> acetoacetyl CoA + succinate Succinyl CoA is from TCA cycle

Question 55

Oxidation of KB- step 3

Answer 55

Acetoacetyl-CoA + CoA —> 2 acetyl CoA Go into TCA cycle

Question 56

Oxidation of KB can be done by

Answer 56

Most tissues - Requires mitochondria Not RBC or liver