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T1 - Phase 1 - Integrated (I) > Cardio - Biochemistry - Fatty Acids; Cholesterol Transport > Flashcards

Cardio - Biochemistry - Fatty Acids; Cholesterol Transport Flashcards

1
Q

Which carbon on a fatty acid is the α carbon?

The β carbon?

The ω carbon?

A

α - carbon 2

β - carbon 3

ω - last carbon

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2
Q

Dissect what each part of this name means:

20:5(Δ5,8,11,14,17) Eicosapentaenoic acid (EPA)

A

20 carbons

5 double bonds

unsaturated (-enoic)

double bonds at carbons 5, 8, 11, 14, and 17

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3
Q

Dissect what each part of this name means:

18:1(Δ9) Octaecenoic acid

A

18 carbons

1 double bond

unsaturated (-enoic)

double bond starting at carbon 9

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4
Q

What type of omega fat is this?

A

Omega-3

(double bond 3rd carbon if you start at the end [omega - ω])

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5
Q

Describe the difference in energy storage timeframes between triglycerides (triacylglycerols) and glycogen.

A

Glycogen = Short-term energy (< 12 hrs)

Triglycerides = Long-term energy (> 12 hrs)

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6
Q

Describe the relative membrane fluidity of saturated and unsaturated fatty acids.

A

Saturated = less fluid (can pack closely)

Unsaturated = more fluid (kinks don’t pack tightly)

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7
Q

Explain the structure of a 16:0 fatty acid.

A

It is a saturated FA with 16 carbons and no double bonds

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8
Q

How would you distinguish saturated vs. unsaturated fatty acids using common nomenclature?

A

Saturated = “anoic acid”

(e.g. 18:0 octadecanoic acid)

Unsaturated = “enoic acid”

(e.g. 18:1(Δ7) trans-7-octadecenoic acid)

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9
Q

What pathologic conditions are implicated with a high consumption of unsaturated fats (e.g. lauric (12:0), myristic (14:0), palmitic (16:0), or stearic (18:0) acid)?

A

Increased risk of atherosclerosis, coronary heart disease, and CVA

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10
Q

Describe the recommended consumption of omega(ω)-fatty acids ratios.

A

Omega-6 and omega-3 between a 1:1 and 4:1 ratio of consumption, respectively.

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11
Q

What are some example health benefits of Omega-3 FA consumption?

A

Protective against:

CVD, unhealthy inflammatory responses, poor neuronal responses in brain and retina, CVA, cancer

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12
Q

Describe the structure of palmitic acid in regards to number of carbons and number of double bonds.

And palmitoleic acid?

And stearic acid?

Place an asterisk next to the saturated fats.

A

16: 0 - saturated*
16: 1 - monounsaturated
18: 0 - saturated*

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13
Q

Describe the structure of oleic acid in regards to number of carbons and number of double bonds.

And α-linolenic acid?

And linoleic acid?

A

18: 1 - monounsaturated
18: 3 - polyunsaturated (ω-3)
18: 2 - polyunsaturated (ω-6)

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14
Q

Name a few ω-3 fatty acids.

A

α-linolenic,

eicosapentaenoic acid (EPA),

docosahexaenoic acid (DHA)

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15
Q

Name a few ω-6 fatty acids.

A

Linoleic acid,

arachidonic acid

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16
Q

Identify if each of the following is either an ω-3 or ω-6 fatty acid (identify the two that are essential with an asterisk):

Docosahexaenoic acid (DHA)

Linoleic acid

α-linolenic

Eicosapentaenoic acid (EPA)

Arachidonic acid

A

ω-3

*ω-6

*ω-3

ω-3

ω-6

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17
Q

How do you distinguish the type of omega acid between Linolenic acid and linoleic acid?

A

Linolenic acid - 1st “n” is 3 letters away from the end = ω-3

Linoleic acid - 1st “n” is 6 letters away from end = ω-6

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18
Q

True/False.

Most naturally occuring double bonds in fatty acids are trans double bonds.

A

False.

Most are cis but processing creates trans double bonds

(extra unhealthy ‘trans fats’)

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19
Q

True/False.

Too many ω-3 fatty acids outcompete ω-6 fatty acids for enzymatic rate limiting steps and are often the cause of decreases in the postitive effects associated with ω-6 fatty acids.

A

False.

Too many ω-6 fatty acids outcompete ω-3 fatty acids for enzymatic rate limiting steps and are often the cause of decreases in the postitive effects associated with ω-3 fatty acids.

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20
Q

From what fatty acid are prostaglandins derived?

A

Arachidonic acid (ARA) (an ω-6 fatty acid)

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21
Q

Which fatty acid stored on a triacylglycerol molecule is often the unsaturated one?

How are fatty acids freed from storage for usage when needed?

A

The one attached to the second carbon on the glycerol backbone;

they are hydrolyzed from the glycerol backbone (and released from their triglyceride storage form)

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22
Q

Describe the functions of triacylglycerols (triglycerides).

A
  1. Long-term energy storage
  2. Cushioning for organs
  3. Thermal insulation (thermogenin and brown fat)
  4. Absorption and transport of fat soluble vitamins (A,D,E,K)
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23
Q

As dietary lipids are ingested and pass into the intestines, how are the gallbladder and pancreas involved in their digestion?

What hormone triggers these reactions?

A

CCK (cholecystokinin) is released from the intestinal mucosa

–>

causing bile (gallbladder) and lipase (pancreatic) secretion

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24
Q

How is dietary fat broken down in the gut?

A

Cholecystokinin causes bile/lipase secretion

–>

Bile emulsifies the fat

–>

Lipase cuts fatty acids off the triacylglycerols (triglycerides)

–>

Intestinal mucosa take up the fatty acids

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25
Q

After being absorbed by the intestinal mucosa, how do fatty acids make their way to the peripheral cells?

A

Triglycerides are

(1) resynthesized,
(2) incorporated into chylomicrons (with cholesterol and apolipoproteins),
(3) released into blood and lymph to reach (but not yet enter!) peripheral cells (e.g. adipocytes)

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26
Q

Describe the makeup of a chylomicron.

A

Triglycerides and cholesteryl esters form the hydrophobic core;

ApoB-48, ApoC-II, cholesterol, and phospholipids make up the hydrophilic exterior

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27
Q

What must a cell do to access the energy stored within chylomicrons?

A

It must increase its secretion of lipoprotein lipase in order to “flag down” the chylomicron and stimulate ApoC-II to breakdown triglycerides

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28
Q

What is the role of lipoprotein lipase?

A

Capillary triglyceride digestion

–> frees fatty acids from chylomicrons to enter cells

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29
Q

Upon making it from the intestinal mucosa to the blood supply of peripheral tissues (e.g. adipocytes), how do fatty acids make it from their triglyceride storage form inside chylomicrons out and into the peripheral tissues?

A

apoC-II (apolipoprotein C-11) on the chylomicron activates lipoprotein lipase (a lipase found in the capillary)

The lipoprotein lipase cuts the fatty acids off glycerol so they can enter the peripheral cells and be oxidized for energy or reesterified into storage triglycerides once more.

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30
Q

What is the function of apoC-II?

Where is it found?

A

To activate lipoprotein lipase;

the chylomicron exterior

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31
Q

What do peripheral tissues (e.g. adipocytes, cardiac muscle) secrete when they need fatty acids for storage and use?

To where is it secreted?

A

Lipoprotein lipase;

the capillary surface (to contact apoC-II on chylomicron surfaces)

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32
Q

Why is steatorrhea (increased fecal lipids) often seen in individuals with cystic fibrosis or bowel resections?

(Why might this be a problem?)

A

Thickening of intestinal mucous

—> digestive lipases not secreted

—> lipids not digested / absorbed

(possibly leading to fat-soluble vitamin and essential fatty acid deficiencies)

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33
Q

A patient has a partial bowel resection. You worry she may develop a fat-soluble vitamin or essential fatty acid deficiency.

What might you advise her to incorporate into her diet in order to mitigate these risks?

A

Short and/or medium-chain fatty acids

–> easier to absorb into the intestinal mucosa (do not require micelle incorporation)

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34
Q

True/False.

Triglyceride (triacylglycerol) synthesis begins with glycerol 3-phosphate.

AND

An activated fatty acid (CoA - S - fatty acid) is then added to the glycerol.

A

True.

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35
Q

Glycerol 3-phosphate is essential to triglyceride synthesis.

What are two ways the liver produces it?

A
  1. Reduction of DHAP (glycerol-P dehydrogenase)
  2. Phosphorlyation of glycerol (glycerol kinase)
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36
Q

Here are two ways that glycerol 3-phosphate can be produced (for triglyceride synthesis).

Which organ(s) use(s) method 1?

Which organ(s) use(s) method 2?

1. Reduction of DHAP (glycerol-P dehydrogenase)

2. Phosphorlyation of glycerol (glycerol kinase)

A
  1. Liver and adipose
  2. Liver only
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37
Q

The liver is capable of forming both preliminary substrates for triglyceride synthesis (DHAP and glycerol).

Describe the conditions in which both molecules are generated (well-fed or fasting)?

A

DHAP is generated during the well-fed state

Glycerol is generated during the fasting state

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38
Q

How are fat storages accessed in the fasting state?

A

Hormone-regulation (glucagon/epinephrine)

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39
Q

Discuss the effect of glucagon and epinephrine on adipose cells.

A

Mobilizes triglycerides for breakdown into free fatty acids and glycerol

(via hormone-sensitive lipase and perilipin)

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40
Q

Glucagon/epinephrine activate G-protein signaling which causes PKA to activate what lipid mobilization components?

A

Hormone-sensitive lipase and perilipin

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41
Q

In regards to fatty acid metabolism, glucagon-activated PKA is responsible for activating what two substances?

A

Hormone-sensitive lipase;

perilipin

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42
Q

What is the role of perilipin?

A

Guards triglycerides inside fat droplets from being hydrolyzed by hormone-sensitive lipase

(until both HSL and perilipin are phosphorylated by PKA)

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43
Q

True/False.

PKA causes a conformational shift in hormone-sensitive lipase to expose triglycerides for activated perilipin to digest.

A

False.

PKA causes a conformational shift in perilipin to expose triglycerides for activated hormone-sensitive lipase to digest.

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44
Q

What happens when PKA phosphorylates the perilipin protein coat in triglyceride storage sites?

A

Perilipin undergoes a conformational change allowing lipase to reach stored triglycerides

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45
Q

During the fasting state, how does hormone-sensitive lipase address the body’s increased energy needs?

A

By breaking down triglycerides into free fatty acids and glycerol

(the FFA enter the bloodstream and are distributed to needy cells)

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46
Q

A fasting myocyte is in need of high-energy free fatty acids. What carries free fatty acids through the bloodstream from adipocytes to myocytes?

A

Serum albumin

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47
Q

If the body breaks down large amounts of triglycerides during fasting, there will be an increased amount of glycerol in the blood and liver.

What will happen to all the serum glycerol once the energy deficit is corrected?

A

All goes to the liver for:

  1. gluconeogenesis (for remaining body needs)
  2. triglyceride synthesis
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48
Q

During what state do muscles secrete lipoprotein lipase?

How is this different than other cells?

A

During the fasting state (when glucose is being saved for the brain);

other cells (liver and adipose cells) use lipoprotein lipase during the well-fed state to replenish energy stores

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49
Q

In the fasting state (low insulin), describe the expression of lipoprotein lipase in adipocytes, hepatocytes, and muscle cells

A

Adipocytes = low expression (provide energy from stores)

Hepatocytes = low expression (provide energy)

Myocytes = high expression (need alternative fuel)

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50
Q

What organ is constantly expressing lipoprotein lipase?

Why?

A

Cardiac cells;

the heart gets 60-90% of its energy from free fatty acids

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51
Q

What is the main pathway for oxidizing fatty acids?

What tissues use this breakdown pathway most frequently?

A

β-oxidation;

tissues with a high energy or metabolic requirement (e.g. cardiac muscle tissue)

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52
Q

What enzyme activates fatty acids?

A

Fatty acyl - CoA synthetase

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53
Q

In triglyceride synthesis, an activated fatty acid (CoA attached) is first attached (via acyl transferase) to the carbon 1 on a glycerol 3-phosphate.

Then, a second activated fatty acid is attached (via acyl transferase) to the carbon 2 on a glycerol 3-phosphate.

What happens next?

A

The phosphate is removed from glycerol 3-phosphate,

then the 3rd carbon receives an activated fatty acid as in the other steps

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54
Q

Where in the cell does β-oxidation take place?

What must occur in order for a fatty acid to be transported into the mitochondria for β-oxidation?

A

The mitochondrial matrix;

fatty acid activation by CoA

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55
Q

The carnitine shuttle exists to take a fatty acid-CoA from the cytosol to the mitochondrial matrix.

What two enzyme are involved in this shuttle system and where are they located?

A

Carnitine acyl transferase I (CAT I) - outer membrane

Carnitine acyl transferase II (CAT II) - inner membrane

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56
Q

At what point is a fatty acid committed to the β-oxidation pathway?

A

Upon entering the mitochondria

(via the carnitine shuttle)

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57
Q

When is β-oxidation used?

It is stimulated by:

A

Fasting state,

exercise;

glucagon, epinephrine

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58
Q

How are fatty acyl - CoA (activated fatty acids) transported into the mitochondria?

A

They are turned into fatty acyl - carnitine,

passed through the carnitine shuttle,

and turned back into fatty acyl - CoA

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59
Q

In what organs is carnitine produced?

What is the body’s main source of carnitine?

A

The liver and kidney;

dietary meats

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60
Q

What is the inheritance pattern of a primary carnitine deficiency?

What causes it?

A

Autosomal recessive;

a defect in either carnitine acyl transferase I or II

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61
Q

A carnitine acyl transferase I (CAT I) deficiency mainly affects what organ(s)?

A

The liver

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62
Q

A carnitine acyl transferase II (CAT II) deficiency mainly affects what organ(s)?

A

Cardiac and skeletal muscle

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63
Q

What is a typical dietary treatment for secondary carnitine deficiencies?

A

High carbohydrates

Low long-chain fatty acids

Carnitine supplementation

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64
Q

Secondary carnitine deficiency typically presents due to what type of conditions?

A

The body not being provided enough carnitine

E.g. Liver disease

Vegetarian diets

Increasing carnitine needs (pregnancy, trauma)

Malnutrition

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65
Q

Which (if any) cells do not utilize β-oxidation pathways?

A

Red blood cells and the brain

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66
Q

What are the 4 repeating reactions of β-oxidation?

A
  1. Oxidation
  2. Hydration
  3. Oxidation
  4. Cleavage
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67
Q

How many Acetyl-CoA can be produced from one round of β-oxidation of palmitate (16:0)?

How many NADH can be produced from one round of β-oxidation of palmitate (16:0)?

How many FADH2 can be produced from one round of β-oxidation of palmitate (16:0)?

A

1 acetyl-CoA

1 NADH

1 FADH2

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68
Q

How many Acetyl-CoA can be produced from complete oxidation of palmitate (16:0)?

How many NADH can be produced from complete oxidation of palmitate (16:0)?

How many FADH2 can be produced from complete oxidation of palmitate (16:0)?

A

8 acetyl-CoA * 10 ATP per Acetyl-CoA = 80 ATP

7 NADH * 2.5 ATP/NADH = 17.5 ATP

7 FADH2 * 1.5 ATP per FADH2 = 10.5 ATP

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69
Q

What is the total energy yield of β-oxidation of a palmitate (16:0) fatty acid?

A

108 ATP

(8 acetyl-CoA, 7 NADH, 7 FADH2)

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70
Q

What is the most common inborn error of metabolism and fatty acid oxidation?

Why is this such a problem for fatty acid oxidation?

A

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

This enzyme is the first oxidation enzyme of fatty acid oxidation and it targets fatty acids of 6 - 10 carbons

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71
Q

Does an individual with medium-chain acyl-CoA dehydrogenase deficiency (MCADD) need to worry if they are eating only long-chain fatty acids?

How is this disorder managed?

A

YES!

Long-chain fatty acids will be oxidized into medium chain lengths and, at that point, will be unable to be broken down;

low fat / high carb diet

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72
Q

How is medium chain acyl-CoA dehydrogenase diagnosed?

It has an association with what fatal infantile disorder?

A

High 6 - 10 mono- and dicarboxylic acids in the blood/urine;

SIDS

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73
Q

When normal β-oxidation is inhibited, medium-chain length fatty acids can be oxidized by __-fatty acid oxidation.

Where does this reaction take place?

A

ω;

the ER of liver and kidney cells.

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74
Q

What is the unique product of ω-fatty acid oxidation?

A

Dicarboxylic acid (succinate)

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75
Q

What is a diagnostic sign of medium-chain acyl-CoA dehydrogenase deficiency (MCADD)?

A

An increase in urine [dicarboxylic acids];

β-oxidation is inhibited and those dicarboxylic acids can’t be oxidized further in mitochondria (so they are ω-oxidized in the ER)

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76
Q

An odd-chain fatty acid can be oxidized but it will end in propionyl-CoA, a 3-carbon structure activated by CoA.

What is the final product of propionyl-CoA after subsequent reactions?

A

Succinyl-CoA - a citric acid cycle intermediate

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77
Q

Even-chain fatty acids end in production of two:

Odd-chain fatty acids end in production of:

A

Acetyl-CoA;

one propionyl-CoA, one acetyl-CoA

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78
Q

What vitamin cofactors are needed to convert propionyl-CoA to succinyl-CoA?

(Note: 2 reactions –> 2 vitamins)

A
  1. Biotin (vitamin B7)
  2. Cobalamin (vitamin B12)
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79
Q

What reaction does biotin facilitate in odd chain fatty acid oxidation?

A

Adds CO2 to propionyl-CoA to form methylmalonyl-CoA

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80
Q

Methylmalonyl-CoA mutase is used in odd chain fatty acid oxidation.

Describe the function and cofactor required by this enzyme.

A

Converts L-methylmalonyl-CoA to succinyl-CoA

Requires vitamin B12 (cobalamin)

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81
Q

What enzymatic defect of odd-chain fatty acid oxidation can lead to methylmalonic acidemia?

A

Defect in methylmalonyl-CoA mutase

(unable to oxidize odd chain fatty acids *inability to replenish key citric acid cycle intermediates)

propionyl-CoA buildup

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82
Q

Where are very long-chain fatty acids oxidized?

What is considered a very long-chain fatty acid?

A

Peroxisomes;

>20 carbons in a chain

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83
Q

What are the two unique aspects of oxidation of very long-chain fatty acids in peroxisomes as compared to normal β-oxidation in the mitochondrial matrix?

A
  1. No carnitine shuttle required for entry into peroxisomes
  2. Initial oxidation produces H2O2 and FAD
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84
Q

Zellweger Syndrome, as well as X-linked adrenoleukodystrophy, result in what primary clinical/laboratory sign?

Why is this?

A

Elevated levels of very long-chain fatty acids;

they are both disorders of peroxisomal very long chain fatty acid oxidation

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85
Q

Explain Zellweger Syndrome.

A

Peroxisomes do not form properly

(very long chain fatty acid cannot occur)

86
Q

What is the problem associated with X-linked adrenoleukodystrophy?

A

Very long-chain fatty acids are unable to cross the peroxisomal membrane to be oxidized

87
Q

What two disorders result from an inability to properly oxidize very long chain fatty acids in the peroxisomes?

A

Zellweger syndrome;

X-linked adrenoleukodystrophy

88
Q

Phytanic acid is a branched chain fatty acid.

Since the branch is on the β-carbon, how is this fatty acid oxidized?

A

α-oxidation

89
Q

What is the final product of α-oxidation?

A

Once the branch has been moved, β-oxidation occurs normally to produce propionyl-CoA (odd chain fatty acid)

90
Q

What enzyme is associated with the branch translocation in α-oxidation?

A

α-hydroxylase

91
Q

Phytanic acid, a branched chain fatty acid, can accumulate in the blood and tissues in a certain disorder.

What is the name of the disease and what major clinical sign is present?

A

Refsum disease (a failure of α-oxidation);

severe neurological dysfunction

92
Q

What neurological signs are associated with Refsum disease (a disorder of branched fatty acid α-oxidation)?

How can the disease be controlled?

A

Polyneuropathy, cerebellar dysfunction, blindness, deafness;

restrict foods with phytanic acid

93
Q

In Refsum disease (a disorder of branched fatty acid α-oxidation), phytanic acid accumulates in blood and tissues. What enzyme is genetically defective?

A

Phytanoyl-CoA hydroxylase

(the α-hydroxylase required to allow branched chain fatty acids to be oxidized)

94
Q

Where does α-oxidation take place?

A

Peroxisomes

*like very long-chain fatty acid oxidation*

95
Q

Where does fatty acid α-oxidation take place? For what type of fatty acids?

Where does fatty acid β-oxidation take place? For what type of fatty acids?

Where does fatty acid ω-oxidation take place? In what situations?

Where does very long chain fatty acid oxidation take place?

A

Peroxisomes, branched fatty acids;

mitochondrial matrix, most fatty acids;

the ER, lack of medium chain oxidation capabilities (e.g. MCADD);

peroxisomes

96
Q

What are the 4 reactions of fatty acid synthesis?

A

*These are exact opposites of fatty acid oxidation*

  1. Condensation (vs. β-ox. step 4 - cleavage)
  2. Reduction (vs. β-ox. step 3 - oxidation)
  3. Dehydration (vs. β-ox. step 2 - hydration)
  4. Reduction (vs. β-ox. step 1 - oxidation)
97
Q

How is malonyl-CoA generated? As part of what process?

A

From acetyl-coA via acetyl-CoA carboxylase;

fatty acid synthesis

98
Q

Where does fatty acid synthesis take place?

A

Cytosol

99
Q

β-oxidation involves the chopping off of __-carbon(s) as _______-CoA.

Fatty acid synthesis involves the addition of __-carbon(s) from _______-CoA.

A

2, acetyl;

2, malonyl (+ release of CO2)

100
Q

Acetyl-CoA is made of __ carbons.

Malonyl-CoA is made of __ carbons.

A

2;

3

101
Q

Describe the significance of acetyl-CoA carboxylase.

A

It is the pivotal enzyme regulated whether the cell is synthesizing or oxidizing fatty acids.

102
Q

When is acetyl-CoA carboxylase activated?

What happens because of its activation?

A

During the well-fed state;

acetyl-CoA is converted to Malonyl-CoA

103
Q

Why is malonyl-CoA so important to fatty acid synthesis?

A

It is the substrate for every round of fatty acid synthesis

(it is basically just acetyl-CoA + CO2)

104
Q

In the well-fed state, what prevents fatty acid chains from being taken into the mitochondria by the carnitine shuttle for β-oxidation?

I.e. What substance is produced and what enzyme does it inhibit?

A

The malonyl-CoA, produced in the first step of synthesis will act as an inhibitor of carnitine acyl-transferase I (CAT I)

  • stops β-oxidation

malonyl-CoA, CAT I

105
Q

How do malonyl-CoA levels change during fasting, and how does this affect cellular β-oxidation?

A

[Malonyl-CoA] is low –>

carnitine acyl-transferase (CAT I) is uninhibited

106
Q

What is the activation state of acetyl-CoA carboxylase during a low-energy state?

A

Acetyl-CoA carboxylase is inactivated

  • increases β-oxidation and the carnitine shuttle system
107
Q

Acetyl-CoA carboxylase (ACC) is regulated through GPCR-coupled hormonal controls. Describe ACCs state when phosphorylated and unphosphorylated.

A

Phosphorylated (PKA) = inactivated (β-oxidation)

Unphosphorylated (PPA2) = active (fatty acid synthesis)

108
Q

How does insulin affect regulation of acetyl-CoA carboxylase?

A

Increased phosphatase activity –>

activates the enzyme to produce malonyl-CoA from the accumulating acetyl-CoA molecules –>

promotes triglyceride storing

109
Q

What is an allosteric activator of acetyl-CoA carboxylase?

A

Citrate

  • increases fatty acid synthesis and the utilization of matrix acetyl-CoAs
110
Q

When insulin is low compared to glucagon, describe the regulation of acetyl-CoA carboxylase (ACC).

A

Increased PKA –>

inactivates ACC –>

promotes β-oxidation to supply cell with needed energy

111
Q

What is an allosteric inhibitor of acetyl-CoA carboxylase (ACC)?

A

Long-chain fatty acids

112
Q

What is an allosteric activator of acetyl-CoA carboxylase (ACC)?

What is an allosteric inhibitor of acetyl-CoA carboxylase (ACC)?

A

Citrate;

long chain fatty acids

113
Q

Approximately what fraction of ketone bodies (formed from acetyl-CoA in the liver) will turn into acetoacetate and β-hydroxybutyrate, respectively?

A

1/3 (acetoacetate);

2/3 (β-hydroxybutyrate)

114
Q

What molecule is the direct precursor to the first ketone body?

Which ketone is this? What else can this first ketone body become?

A

Acetyl-CoA;

acetoacetate (1/3 of ketone production);

β-hydroxybutyrate (2/3 of ketone production);

115
Q

Under what conditions will cells use ketone bodies?

A

Prolonged fasting (low glucose levels)

116
Q

Discuss why “acetone breath” is a sign of someone with Type I diabetes.

A

Glucose can’t be brought into cells –>

free fatty acids are mobilized and oxidized –>

fatty acids convert to ketone bodies –>

spontaneous decarboxylation produces acetone

117
Q

___________ can be converted into acetoacetate (1/3 of ketone bodies).

___________ can be converted into β-hydroxybutyrate (2/3 of ketone bodies).

A

Acetyl-CoA,

acetoacetate

118
Q

HDL takes ______ back to the ______.

VLDL takes ______ to the ______.

LDL takes ______ to the ______.

A

cholesterol, liver

triglycerides, peripheral tissues.

cholesterol, peripheral tissues or back to the liver.

119
Q

What lipoprotein takes cholesterol from the peripheral tissues back to the liver (reverse cholesterol transport)?

A

High-density lipoproteins (HDLs)

(recover excess cholesterol from extrahepatic tissue and carry it back to the liver for excretion or recycling)

120
Q

After chylomicron triglycerides are depleted by peripheral tissues (via apoC-II and lipoprotein lipase), what is the fate of the chylomicrons?

A

They travel to the liver (as chylomicron remnants)

121
Q

What two carriers deliver triglycerides to the peripheral tissues?

(Hint: one comes from the intestines; one comes from the liver.)

(And cholesterol?)

A

Chylomicrons (intestinal)

VLDLs (from the liver)

(cholesterol - via LDL)

122
Q

What tissue types make ApoA-1?

What tissue type makes ApoB-48?

What tissue types make ApoB-100?

What tissue types make ApoC-II?

What tissue types make ApoE?

A

The liver and the intestines;

the intestines;

the liver;

the liver;

the liver

123
Q

What protein is secreted by peripheral cells to utilize the triglycerides and cholesterol carried by very low-density lipoprotein complexes (VLDLs)?

A

Lipoprotein lipase

124
Q

Once a very low-density lipoprotein complex (VLDL) has been depleted of its triglycerides, what is its fate?

A

VLDL remnants return to the liver

OR

are converted into low-density lipoprotein (LDL) complexes

–> delivers cholesterol to the tissues

125
Q

Describe the makeup of a low-density lipoprotein (LDL).

A

A VLDL that has delivered its triglycerides and is now especially enriched with cholesterol

(i.e. the triglyceride to cholesterol ratio has decreased; it can now return to the tissues and drop off cholesterol)

126
Q

After a very low-density lipoprotein complex (VLDL) is converted to a low-density lipoprotein complex (LDL), what is the purpose of that LDL?

A

Distribute cholesterol to extrahepatic tissues

OR

return to the liver as a more depleted form of lipoprotein complex

127
Q

How can you remember that ApoB-48 is involved in assembly and secretion of chylomicrons from the intestinal mucosa?

A

It’s for (4)what youate(8)

128
Q

What does ApoE do for chylomicrons, HDL, VLDL, and LDL?

A

It basically just serves as a ligand for these complexes to be endocytosed by the liver

129
Q

ApoA class apolipoproteins are found in what structures?

And ApoB?

And ApoC?

A

ApoA - HDL

ApoB - VLDL, LDL, chylomicrons

ApoC - VLDL, chylomicrons

130
Q

By what apolipoprotein is the assembly and secretion of very low-density lipoprotein complexes (VLDLs) facilitated?

A

ApoB-100

131
Q

By what apolipoprotein is the assembly and secretion of chylomicrons facilitated?

A

ApoB-48

132
Q

What does ApoB-48 do?

What does ApoB-100 do?

What does ApoC-II do?

A

B-48 –> chylomicron assembly and secretion from intestines

B-100 –> VLDL assembly and secretion from liver; ligand for LDL receptor

C-II –> activates lipoprotein lipase

133
Q

ApoA-1 is a structural component of what type of complex?

A

HDL particles

134
Q

Where are chylomicrons synthesized?

What apolipoprotein(s) is associated with immature chylomicrons?

These chylomicrons mature as what complex attaches ApoE and ApoC-II to the chylomicrons surfaces?

A

Intestinal mucosa;

ApoB-48;

HDL

135
Q

From what complex do nascent chylomicrons (ApoB-48) and VLDLs (ApoB-100) receive their additional external apolipoproteins (ApoC-II, ApoE) and become mature chylomicrons and VLDLs, respectively?

A

HDL

136
Q

True/False.

Chylomicrons are 90% triglyceride with a only a small portion as cholesterol esters.

AND

VLDLs are 60% triglyceride with a only a moderate portion as cholesterol esters.

A

True.

137
Q

The liver takes up chylomicron remnants via ______ proteins.

Extrahepatic tissues and/or the liver takes up LDL remnants via ______ proteins.

A

ApoE;

B-100

138
Q

What is the role of PCAT (also called LCAT)?

A

Attaches extrahepatic tissue cholesterol to fatty acids in HDL particles

*part of reverse cholesterol transport*

139
Q

What apoprotein is a structural component of HDL and activates PCAT so that HDL can perform reverse cholesterol transport?

A

ApoA-1

140
Q

What does the ApoB-100 apolipoprotein do for VLDLs?

What does the ApoB-100 apolipoprotein do for LDLs?

A

Assembly and secretion from the liver;

endocytosis into the liver

141
Q

What is the primary tissue source of ApoB-100 apoproteins?

A

Liver

142
Q

What is the primary tissue source of ApoC-II?

A

Liver (attached to HDLs)

143
Q

When a chylomicron or a VLDL is traveling through the capillaries, what surface apoprotein will activate the cells’ lipoprotein lipase?

A

ApoC-II

144
Q

What lipoprotein complexes utilize ApoC-II for lipoprotein lipase activation?

A

All of them

(i.e. chylomicrons, VLDLs, LDLs, and HDLs)

145
Q

What is the primary tissue source of ApoE apoproteins?

A

The liver

146
Q

Describe the role of ApoE apoproteins when attached to a lipoprotein complex.

A

Ligand for LDL receptors

147
Q

What lipoprotein complexes utilize ApoE apoproteins?

A

All of them

(chylomicron remnants, VLDL, LDL, HDL)

148
Q

When a low-density lipoprotein (LDL) binds to the target cell, what is used as the ligand for the LDL (describe its process of endocytosis)?

A

Binds via ApoB-100 –>

LDL is brought in via endosome –>

it is degraded by lysosomes –>

products are used up in the cell (fats, cholesterol, amino acids, etc.)

149
Q

What enzyme synthesizes new cholesterol in the cell?

A

HMG-CoA reductase

150
Q

HMG-CoA reductase synthesizes cholesterol.

What will happen if an excess of low-density lipoprotein (LDL) is brought into the cell?

A

Oversupply of cholesterol –> inhibits HMG-CoA reductase

151
Q

What two processes are inhibited by an oversupply of cholesterol in the cell?

A
  1. Production of new cholesterol (HMG CoA reductase)
  2. Synthesis of new LDL receptors for cell membrane
152
Q

How do cells protect against an oversupply of cholesterol brought in by low-density lipoprotein (LDL) endocytosis?

A

Activation of ACAT –>

turns cholesterol into cholesteryl esters (storage form)

153
Q

What is the storage form of cholesterol in a cell?

A

Cholesteryl esters

154
Q

Why are low-density lipoproteins (LDL) considered “bad” cholesterol?

A
  1. They can become oxidized (OxLDL) and damage endothelial cells
  2. They deliver cholesterol to peripheral tissues for storage
155
Q

Following the oxidation of low-density lipoproteins (OxLDL), what cascade would put someone at risk for atherosclerosis?

A

Macrophages respond to endothelial injury –>

engulf OxLDL –>

become foam cells and release products that form atherosclerotic plaques

156
Q

Describe familial hypercholesterolemia (type II hypercholesterolemia).

What is its inheritance pattern?

A

Dysfunctional LDL receptor –>

persistently high LDL cholesterol

Autosomal dominant

157
Q

What is another name for type II hypercholesterolemia?

A

Familial hypercholesterolemia (autosomal dominant dysfunction in LDL receptors)

158
Q

A young patient presents with premature atherosclerosis and significantly elevated serum LDL, what are some molecular etiologies you might consider in this patient?

A
  1. Dysfunctional or degraded LDL receptor
  2. Defective ApoB-100
159
Q

What fasting LDL cholesterol levels would you suspect in someone who has heterozygous familial hypercholesterolemia (FH)?

A

250 - 500 mg/dL

(normal = 100 mg/dL)

160
Q

What fasting LDL cholesterol levels would you suspect in someone who has homozygous familial hypercholesterolemia (FH)?

A

500 - 1200 mg/dL

(normal = 100 mg/dL)

161
Q

What is another name for type III hyperlipoproteinemia?

A

Familial dysbetalipoproteinemia

162
Q

What is the recommended (healthy) ratio of HDL:LDL cholesterol?

A

> 0.4

163
Q

Describe the clinical signs of familial dysbetalipoproteinemia.

A

Elevated blood cholesterol and triglyceride levels

164
Q

Discuss the underlying pathology of type III hyperlipoproteinemia and how that results in the clinical signs of this disease.

A

Defective or deficiency of Apolipoprotein E (ApoE) –>

Reduces the body’s ability to clear LDL and chylomicron remnants from the blood

165
Q

Describe the role of microsomal triglyceride transfer protein (MTTP) and its role in B-type apoprotein complexes.

It is deficient in what disorder?

A

Essential for synthesis of B-type apolipoproteins;

abetalipoproteinemia

166
Q

What surface proteins would be missing in an individual with abetalipoproteinemia?

A

ApoB-48 and ApoB-100

167
Q

What are two other names for abetalipoproteinemia?

A

Bassen-Kornzweig Syndrome or microsomal triglyceride transfer protein (MTTP) deficiency

168
Q

Discuss the signs and symptoms of an individual with Bassen-Kornzweig Syndrome (abetalipoproteinemia) and why these would be the symptoms.

A

Severe malabsorption of fats and ADEK vitamins

Fatty enterocytes

Acanthocytosis (of RBCs)

Deficiency in B-type apoproteins needed to make chylomicrons, VLDLs, and LDLs

169
Q

For many metabolic disorders involving fatty acids and cholesterol, why are medium-chain fatty acids a recommended diet in treatment?

A

They can be easily absorbed by the body without micelle production –>

less intestinal symptoms and more vitamin absorption

170
Q

Type I Niemann-Pick disease includes what two subtypes?

A

Type A and B Niemann-Pick diseases

171
Q

Type II Niemann-Pick disease includes what two subtypes?

A

Type C and D Niemann-Pick diseases

172
Q

Niemann-Pick diseases are lysosomal storage disorders.

Describe the cellular effect of Type C Niemann-Pick disease.

A

Excessive cholesterol buildup in lysosome

173
Q

Discuss why one would see the histological signs associated with Niemann-Pick Type C disease.

A

Buildup of cholesterol in lysosome because cholesterol releasing genes are mutated.

Cholesterol stays sequestered in the endosome which activates cellular mechanisms to bring more LDLs containing cholesterol into the cell

174
Q

What genes are mutated in Niemann-Pick Type C disease? What are their functions?

A

NPC1 and NPC2

Release cholesterol from the endosome after endocytosis

175
Q

By what transportation mechanism do HDL perform reverse cholesterol transport?

A

ABCA1 transporter –>

helps HDLs take up free cholesterol from peripheral tissues

176
Q

What disorder desults from a defect in the ABCA1 transporter?

What does this transporter do?

A

Tangier Disease;

helps HDLs take up free cholesterol from peripheral tissues

177
Q

What is another name for Tangier disease?

A

Familial HDL deficiency

178
Q

Discuss several consequences that are associated with the deficient ABCA1 transporter found in Tangier disease.

A

Cholesterol accumulation in peripheral tissues

Reduced HDL particles

Lack of ApoC-II proteins on chylomicrons and VLDLs

179
Q

What percentage of membrane-bound cholesterol is found in the brain?

A

~25%

180
Q

What is the most abundant apolipoprotein in the CNS?

A

ApoE

181
Q

ApoE proteins come in several allelic forms.

What form is the most common?

A

ApoE-3

182
Q

Which two allelic forms of apoprotein E are indicated in Alzheimer’s disease onset?

A

ApoE-3 and ApoE-4

183
Q

Greater than what ideal cholesterol:HDL ratio will increase an individual’s risk of cardiovascular disease?

A

> 4:1 = increased risk

184
Q

What combination of abnormalities are typical of an atherogenic dyslipidemia profile?

A

Increased triglycerides

Increased LDL cholesterol

Decreased HDL cholesterol

185
Q

What is the most common genetic defect of cholesterol biosynthesis?

A

Smith-Lemli-Opitz Syndrome (SLOS)

186
Q

Describe the causative defect in Smith-Lemli-Opitz Syndrome.

A

Cholesterol synthesis enzyme deficiency –>

causes buildup of 7-DHC, the last substrate in the pathway

187
Q

Smith-Lemli-Opitz Syndrome has been shown to cause fetal development defects, specifically, in what cholesterol modification protein?

A

Hedgehog (Hh) protein

188
Q

How might a patient with Smith-Lemli-Opitz Syndrome (SLOS) appear?

A

*Fetal development defect* –> morphogenic abnormalities (microcephaly, congenital heart defects, polydactyly)

189
Q

What is the most common dietary treatment for a patient with elevated cholesterol levels?

A

Restrict long-chain fatty acids (LCFA)

Increase carbohydrate intake

190
Q

Which fatty acids are derived from α-linolenic acid (ALA)?

A

Eicosapentaenoic acid (EPA) Docosahexaenoic acid (DHA)

(omega-3s)

191
Q

Arachidonic acid is derived from what omega-6 fatty acid?

A

Linoleic acid

192
Q

Eicosanoids are signaling molecules used throughout your body. Eicosanoid synthesis utilizes oxidation of what molecule?

A

Arachidonic acid

193
Q

Which omega-3 fatty acid is required for proper retinal/neural function at all stages of development?

A

Docosahexaeoic acid

(both it and ARA are often fortified in milk products)

194
Q

Which omega-6 fatty acid is the precursor for eicosanoid synthesis?

A

Arachidonic acid (20:4)

195
Q

Arachidonic acid is an omega-__ fatty acid.

It can often be found on the __ carbon of the glycerol backbone in membrane phospholipids.

A

6;

2nd

196
Q

What is the ideal omega-3:omega-6 ratio?

A

1:4

(in Western diets, it is often much lower –> e.g. 1:15)

197
Q

Why do trans-unsaturated fats behave more like staturated fats than cis-unsaturated fats?

A

The trans double bond doesn’t ‘kink’ the tail like a cis double bond does

198
Q

Soon after eating a meal, will hormone-sensitive lipase be activated or inactivated?

Will capillary lipoprotein lipase be activated or inactivated?

A

Inactivated;

activated

199
Q

In the fasting state, what tissues are secreting and/or packaging / distributing fatty acids for muscle use?

A

Adipose (via hormone-sensitive lipase);

the liver (packaging adipose fatty acids into VLDLs)

200
Q

What substance surrounds fat droplets in the adipose and must be phosphorylated in order for hormone-sensitive lipase to access the triglycerides?

What hormonal pathway causes this phosphorylation?

A

Perilipin;

glucagon/epinephrine –>GPCR –> Adenylyl cyclase

–> PKA

201
Q

Why do myocytes not secrete much lipoprotein lipase in the well-fed state?

Why do myocytes secrete lipoprotein lipase in the fasting state?

A

They can use glucose here;

glucose is preferentially saved for the brain

202
Q

During the fasting state, adipocytes secrete fatty acids that are carried in the blood on serum _______. What two tissues in particular pick up these fatty acids?

A

Muscle;

the liver (for repackaging as VLDLs or for gluconeogenesis; or eventually for storage if the fasting state ends)

203
Q

What type of fatty acids can be therapeutic options as they do not need to be incorporated into micelles to be absorbed and are relatively easily absorbed in the gut?

A

Short- and medium-chain fatty acids

204
Q

What deficiency is most likely to result in hypoketotic hypoglycemic encephalopathies?

How is this prevented?

A

Carnitine deficiencies;

carnitine supplementation, high carbohydrate / low long-chain fatty acid diets

205
Q

Will all of the following be affected with equal difficulty in entering the mitochondria in an individual with a carnitine deficiency?

Short-chain fatty acids

Medium-chain fatty acids

Long-chain fatty acids

Very long-chain fatty acids

A

No;

long- and very long-chain fatty acids are affected most

(but short- and medium-chain fatty acids aren’t reliable as sole sources of energy)

206
Q

What type of acidosis is most likely in a child with medium-chain acyl-CoA dehydrogenase deficiency (MCADD)?

A

Dicarboxylic acidosis

(due to shunting to ω-oxidation in the ER)

207
Q

What is one of the most common inborn errors of metabolism and the most common disorder of β-oxidation?

A

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

(often results in dicarboxylic acidosis of 6- to 8-carbon chains due to shunting to ω-oxidation)

208
Q

True/False.

Diabetic ketoacidosis is a result of increased acetyl-CoA / ketone production via increased glycolysis.

A

False.

Diabetic ketoacidosis is a result of increased acetyl-CoA / ketone production via increased

β-oxidation.

209
Q

Are statins an effective therapy for individuals that are heterozygous for familial hypercholesterolemia?

Are statins an effective therapy for individuals that are homozygous for familial hypercholesterolemia?

A

Yes;

no –> apheresis instead

210
Q

True/False.

A diet high in trans fats will lead to a dylipidemic profile, including low HDL levels.

A

True.

211
Q

What is the ideal HDL:LDL ratio?

A

> 0.4

T1 - Phase 1 - Integrated (I) (28 decks)

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