Lipid and Ketone Body Metabolism

Question 1

what are Dietary lipids?

Answer 1

well primarily they are: Triglycerides, triacylglycerols (TG, TAG): 3 fatty acid chains esterified to a glycerol backbone

Question 2

What is needed in order to digest TGs?

Answer 2

1. Bile salts (gallbladder) emulsify fat 2. Pancreatic lipase (needs a co-lipase to function) acts to remove 2 of the FAs (left with 2FAs + monoglycerol) 3. Bile salts form micelles 4. micelles cross the intestinal epithelium 5. FAs activated and recombine with monogycerol to form TGs again 6. TG combines with AboB48 and other lipids to form chylomicrons 7. chylomicrons leave the intestinal cells, enter lymph circulation, then enter blood circulation

Question 3

what transports DIETARY lipids

Answer 3

chylomicrons = **TG + ApoB48 + cholesterol + lipid monolayer + peripheral apoprotein

Question 4

How do we transport ENDOGENOUS lipids

Answer 4

FA from the liver are turned into TGs and then put into blood for transport by VLDL *insulin stimulates the liver to synthesize VLDL

Question 5

How to we get the FAs that are being transported through the blood by chylomicrons and VLDL into the appropriate tissues for storage?

Answer 5

Lipoprotein lipase (LPL) releases fatty acids from lipoproteins to tissues – located on inner surface of capillaries in skeletal muscle tissue and adipose tissue (LPL in adipose tissue has a high Km -low affinity- so its most active in fed state) (LPL in muscle tissue has a low Km -high affinity- so it’s always very active) *muscle LPL can cleave FA when concentrations of chylomicrons are low

Question 6

LPL (lipo-protein lipase)

Answer 6

Lipase regulated by: insulin functions to store FA

Question 7

HSL (hormone-sensitive lipase)

Answer 7

Lipase regulated by: Glucagon, epinephrine, cortisol functions to release FA for use as fuel

Question 8

When FAs are released into the blood, either by LPL or HSL, how are they transported?

Answer 8

on albumin that’s why it’s the most abundant blood protein

Question 9

Sickle cell can overwhelm the body’s capability to excrete bilirubin. What are consequences of not getting rid of bilirubin fast enough?

Answer 9

accumulating bilirubin/heme pigment in the skin causes jaundice -accumulating bilirubin/heme can cause gallbladder stones (poor fat absorption if blocked gallbladder)

Question 10

What might you expect if each of the lipases is not working? -LPL -HSL -Pancreatic lipase

Answer 10

1. (Can’t utilize fat for energy* only if you have exhausted adipose supplies first) (but can still get into intestinal epithelial and into blood) so increase in chylomicrons and LDL leads to increase in atherosclerosis 2. Unable to release FA from adipose stores (you will stay fat). The free FA in blood are not sufficient to supply muscle so we would also see weak muscles 3. Poor fat digestion (fat in stool). You would be more dependent on your bodies ability to produce lipids. So would you be recommended to eat high fat diet? FUCK NO

Question 11

Name the most common fatty acids ingested as TGs (so there would be 3 in a TG)

Answer 11

palmitate, oleate, stearate (with glycerol as backbone) -note these are ‘long chain FA’ (16 carbons or longer)

Question 12

So we need to import these FAs from the blood into the matrix for oxidation right? HOW THE FUCK do we do THAT? (assuming aerobic conditions)

Answer 12

(we want to get FAs into most cells, not RBCs though, they can’t use it) pic slide23

Question 13

Is FA activation spontaneous?

Answer 13

HELL NO. requires the equivalent of 2 ATP for activation! Note ATP is cleaved twice down to AMP

Question 14

Details of Carintine shuttle? pic slide 25

Answer 14

CPT I complex – gets us in a form that can be shuttled across the membrane Carnitine acylcarnitine translocase (CAT) actually responsible for the transport CPT II – removes the carnitine, no we can get oxidation

Question 15

Alrighty, now the FAs are in the mitochondria matrix, what now? what are we doing?

Answer 15

Beta Oxidation! *The beta oxidation spiral takes FA and generates Acetyl CoA and NADH note: since we are forming NADH it is a good bet that there will be dehydrogenase enzymes in the B-oxidation spiral

Question 16

The energy yield from β-oxidation of FA is GREAT! what is it?

Answer 16

Number of clevages = n N= #of NADH and FADH2 N+1= # of acetyl CoA **(1.5 ATP/FADH2) **(2.5 ATP/NADH) ***(10 ATP per acetyl-coA)***

Question 17

Ex: 16-C palmitic acid (do the math bitch)

Answer 17

7 cleavages = 7 FADH2 and 7 NADH 7 x 1.5 ATP/FADH2 + 7 x 2.5 ATP/NADH = 28 ATP Subtract 2 ATP for cleavage of 2 Pi bonds 8 acetyl-coA to use in TCA cycle ~10 ATP per acetyl-coA (80 ATP) So a total of 26 + 80 = 106 ATP per palmitic acid.

Question 18

What if the FA is an odd-chain FA? 17-C palophagoicbuthole acid

Answer 18

after the last cycle you get an Odd chain Propionate (a 3 C molecule) instead of acetate (2 C molecule)

Question 19

One major Regulation of β-oxidation, and 3 others?

Answer 19

-Biggest factor-*Demand for energy (fasting, exercise) stimulates B-oxidation (*THIS IS THE RATE LIMITING STEP OF B-oxidation, so adding a caratine supplement wont help you burn fat/use more energy unless you exercise/fast) *AMP stimulates (indicating cells energy needs are not met!) -Malonyl CoA inhibits -insulin inhibits (via stimulating Malonyl CoA) -obviously buildup of products inhibit (bc the cells energy need are met, we don’t need B-oxidation (energy) NADH inhibits ATP inhibits Acetyl CoA

Question 20

Which tissues oxidize FA completely to CO2 and H20?

Answer 20

muscle (uses KB during brief fast, then switches to FAs during a prolonged fast) kidney

Question 21

Which tissues oxidize FA partially (to acetyl CoA), then convert Acetyl CoA to Ketone Bodies?

Answer 21

LIVER

Question 22

Tissues that don’t use a lot of FAs

Answer 22

Brain (very limited use, uses KB instead during long fast) RBCs (NOT at all) Adipocytes (NOT at all)

Question 23

Where are KB made in the body?

Answer 23

Liver produces but cannot use ketone bodies (FAs to Acetyl CoA (B-Oxidation) to Acetoacetate)

Question 24

What is spontaneous decarboxylation?

Answer 24

Acetoacetate can lose CO2 spontaneously and form acetone in the blood This results in ketoacidosis (acetone smell on the breath is a giveaway!)

Question 25

What do we mean when we say that the brain or muscle USE ketone bodies?

Answer 25

THey convert KBs back to acetyl-coA, which enters TCA cycle for oxidation. (to generate ATP! energy!) so really the tissue are getting more acetyl CoA, that’s what they VANT!

Question 26

distinguish prolonged vs. brief fast?

Answer 26

3 DAYS is the cut off for a prolonged FAST (I think longer than 3 days?) hopefully she doesnt use exactly 3

Question 27

As fasting goes on (I get so hungry)! What is happening to the fuel in my blood?

Answer 27

-glucose drops! (but levels off at the bottom of the homeostatic range - 80ish) -slight increase of FA (actually there is a huge increase in the freeing of FA to be use for energy, its just that we only see a slight increase in the blood because we are using them up quickly!) -slight increase in acetoacetate (same rationale as FA increase - we are using em up to generate Acetyl CoA) and maybe some will spontaneously decarboxylate -B-hydroxybutyrate -spike super high (why?) because its the other Ketone body and it’s produced 1:1 with acetoacetate. BUT it’s not used for energy oxidation and it is stable (no spontaneous decarboxylation)

Question 28

Regulation KB synthesis

Answer 28

-like FA synthesis, it’s based on energy needs: *biggest stimulator -energy demand (long fast / exercise) -AMP - stimulates synthesis -high ATP, NADH, insulin (ALL INHIBIT SYNTHESIS OF KB)

Question 29

WHat the heck is alternate Ketone body metabolism??

Answer 29

Just know that the carbon skeletons of some AA can produce Ketone bodies ketogenic amino acids = leucine, lysine ketogenic and glucogenic = isoleucine phenylalanine tryptophan tyrosine threonine

Question 30

Fatty acids will be the major source of fuel for most tissues of the body: A. 2 hours after a meal B. 30 minutes after a meal C. Overnight while asleep D. Running the 1st mile of a marathon E. Running the last mile of a marathon

Answer 30

A. Glucose – from glycogen break down B. Glucose – coming from eating C. Glucose – from glycogen break down (and some from gluconeogenesis?, and a bit from FA) D. Glucose – from liver glycogenolysis and muscle glycogenolysis E. FA –from adipose tissue Epinephrine, HSL stimulation

Question 31

*Explain how a defect in fatty acid oxidation could lead to decreased blood glucose levels.

Answer 31

Prolonged fasting – FA oxidation is providing energy to skeletal muscle (BUT its also proving energy for gluconeogenesis to continue!!) No FA oxidation = No energy for gluconeogenesis = decreased blood glucose -glucagon levels would be high -insulin levels would be low

Question 32

What if your blood glucose is too high? Too low?

Answer 32

neuropathy and cardiovascular disease(high glucose alters certain protein in your blood) if its too low weak, tired, pass out, coma

Question 33

What are the effects of insulin on the muscle and adipose tissues?

Answer 33

Glucose disposal (insulin helps bring glucose into tissue): TG synthesis glycogen synthesis Active glycolysis

Question 34

What is (are) the major organ(s) acted on by glucagon?

Answer 34

Glucagon works on the live glycogenolysis gluconeogenesis

Question 35

Note that changes in blood glucose also affect fatty acid metabolism: when blood sugar increases =

Answer 35

FA synthesis is active

Question 36

Note that changes in blood glucose also affect fatty acid metabolism: when blood sugar decreases=

Answer 36

FA oxidation is active

Question 37

Fuel usage by different tissues in fed state

Answer 37

Question 38

How does the TCA cycle relate to glycolysis, fatty acid oxidation, ketone body oxidation, and amino acid oxidation?

Answer 38

Each of these metabolic pathways produces Acetyl CoA which enter the TCA cycle for oxidation as oxaloacetate

Question 39

What molecule(s) connect the above pathways to oxidative phosphorylation for ATP production?

Answer 39

NADH, FADH2

Question 40

Brief/early fasting

Answer 40

Question 41

Prolonged fasting (Keep in mind, blood glucose must still be kept in homeostatic range)

Answer 41

Question 42

How does HSL become active?

Answer 42

Glucagon can convert inactive HSL into active HSL

Question 43

A patient has low insulin, what is the effect of low insulin? Do we see evidence of this in our patient’s lab results?

Answer 43

-Insulin stimulates LPL expression and inhibits HSL activity; -Low LPL would lead to high serum VLDL and chylomicrons -Elevated glucagon would also contribute FA to blood (she will have fatty serum)

Question 44

What are contributing factors to her hyperglycemia? (A patient has low insulin)

Answer 44

Inc. glucagon = increased glycogenolysis and gluconeogenesis low insulin = existing glucose from meal not disposed from blood to tissues

Question 45

Why does she have ketoacidosis? (A patient has low insulin)

Answer 45

She is using FA as her major fuel (increased lipolysis is providing that fuel – so increased KB formation in liver – decarboxolation of aceotoacetate and the CO2 dissolving in her blood is making her blood more acidic.

Question 46

DO we see ketoacidosis in type II diabetes?

Answer 46

Not, not really. In type II diabetes the insulin deficiency is not uniform across all tissues, some tissues do respond to insulin, so you don’t get to level of KB that type I does

Question 47

A 15 year-old diabetic is brought to the ED in diabetic ketoacidosis (DKA). She is barely conscious, has been vomiting, and has acetone on her breath. A urine sample shows greatly elevated KB. Which of the following is true for this patient? True or false: -Blood glucose is likely much less than 80 -Serum FA levels will be sig depressed -She should be given a glucagon infusion to stimulate glycogenolysis and gluconeogenesis -She should be given a glucose infusion -She should be given insulin to decrease her KB

Answer 47

Type I diabetes (ketoacidosis) -Blood glucose is likely much less than 80: FALSE it would be elevated -Serum FA levels will depressed; FALSE we would expect an increase, this is her source of energy -She should be given a glucagon infusion to stimulate glycogenolysis and gluconeogenesis: FALSE, this would be worse -She should be given a glucose infusion: FALSE this would be super-bad -She should be given insulin to decrease her KB: TRUE, this would decrease her KB by allowing her body to recognize glucose, therefore she can use glucose as fuel and she’s less dependent on FA, and producing less KB