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Lecture 23 Flashcards

Fatty Acid oxidation nuts and bolts (79 cards)

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1
Q

How are huskies like a fat bruning machine?

A

Huskies participate in the Iditarod Trail Sled Dog Race, annual dogsled race run in March between Anchorage and Nome, Alaska, U.S.
The trail is ~1,800 km long.

  • They need to have excellent metabolism to compete in this race.
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2
Q

where do huskies draw energy from to begin with?

A

During the first few days of racing, sled dogs draw energy from glycogen stored inside muscle cells.

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3
Q

What do huskies switch to after the first few days?

A

But instead of depleting glycogen stores and tiring the muscles, the animals suddenly switch to a glycogen-sparing metabolism.

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4
Q

where do huskies begin drawing energy from?

A

Huskies start drawing energy from sources outside the muscle.

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5
Q

What is it likely that muscles do to burn fat?

A

They start drawing energy from sources outside of the muscles.
- Muscle cells likely start extracting fat directly from the blood and somehow transport this fat across the cell membranes and into the cells, where it can be burned as fuel

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6
Q

Why is digestion of lipids difficult?

A

The digestion of lipids is made difficult due to their hydrophobicity.

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7
Q

What is the primary source of fatty acids?

A

In humans, dietary triacylglycerols (TAGs) are the primary source of fatty acids used as metabolic fuel.

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8
Q

How are TAGs transported?

A

TAGs are carried by lipoproteins to tissues where they are hydrolyzed extracellularly by lipoprotein lipase

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9
Q

How are TAGs in adipose tissue mobilized?

A

TAGs that are stored in adipose tissue are mobilized by intracellular lipases, including hormone-sensitive
lipase.

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10
Q

How do mobilized adipose tissue fatty acids travel through the bloodstream?

A

The mobilized fatty acids travel through the bloodstream, not as part of lipoproteins, but bound to
albumin, a 66-kD protein that accounts for about half of the serum protein.

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11
Q

Why is the concentration of free fatty acids low?

A

The concentration of free fatty
acids in the body is very low because these molecules are detergents.

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12
Q

Cell requirement for lipids?

A

Every cell needs lipids for membranes, energy, regulatory systems etc.
* Most lipids are not water-soluble
* Structural proteins, source of ATP, signalling proteins and more!

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13
Q

We need what kind of transport for lipids?

A

The body needs water-soluble
transport forms for lipids in the
circulation.
Distinct types of lipoproteins are
used to achieve different
transport pathways.

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14
Q

Water-insouble fats are packaged how?

A

Water-insoluble fat is packages into soluble lipoprotein particles.

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15
Q

Proteins in the membrane of fat lipoprotiens are..?

A

They are distinct based on what’s being packaged and also act as conecotors to their respective lipoprotien receptors.

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16
Q

What lipids are inside a lipoprotein?

A

Very polar lipids tat are required tp be stored in the highly hydrophbic core.

  • Cholesterol esters and TAG
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17
Q

What is in the amphipathic shell?

A
  • Phospholipid
  • Cholesterol
  • Apolipoproteins
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18
Q

What is in the hydrophobic core of lipoproteins?

A
  • Triacylglycerols (TAGs)
  • Cholesteryl esters
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19
Q

Where are unesterified fatty acids transported?

A

Unesterified fatty acids are transported in complex with the soluble protein, albumin. NOT lipoproteins.

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20
Q

What lipids compose chylomicrons and what do they transport?

A

Chylomicrons are mainly composed of TAG and transport TAG from the diet to the adipose tissue

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21
Q

What is chylomicron?

A

It is produced by gut cells, internal sites as they are repackaging the lipids that we take in through the diet for delivery to the rest of the body for use.

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22
Q

VLDL lipid composition and transport?

A

Very low density lipoproteins mostly contain TAG and have some cholesterol.

They transport TAG from the liver to the adipose tissue.

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23
Q

LDL lipids and transport?

A

Low density lipoproteins are cholesterol rich and transport cholesterol from the liver to the periphery.

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24
Q

HDL lipids and trasport?

A

High density lipoproteins contain mostly protein and some cholesterol, and transport cholesterol from the periphery to the liver.

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25
Each class of lipoproteins contains..?
Each lipoprotein class has characteristic apolipoproteins that serve as identifiers, for targeting and for enzyme activation
26
How is dietary fat transported?
Dietary fat is transported by chylomicrons.
27
How is fat packaged into chylomicrons?
Intestinal cells package dietary fat into chylomicrons (mostly TAGs, some cholesterol). - Most of the TAGs are delivered to adipose tissue for storage. - Chylomicron remnants are taken up by the liver.
28
Where are chylomicrons during fasting?
Chylomicrosn are absent during fasting,
29
Uptake of TAG is indirect?
The uptake of TAGs into adipose tissue and muscle cells is indirect after hydrolysis to glycerol and fatty acids. - In muscle they are mostly used for ATP synthesis and B-oxidation
30
Endogenous lipids - LDL contains..?
LDL contain cholesteryl ester and cholesterol and deliver cholesterol to peripheral tissues. - LDL can be taken up into macrophages in the arterial wall = risk for atherosclerosis
31
Endogenous lipids - VLDL?
VLDL are made by the liver, which synthesizes TAG and cholesterol and secrets them as VLDL. - Adipose tissue and muscles take up fatty acids from hydrolysis of VLDL-TAG. This is similar to chylomicrons
32
What is the VLDL remnant?
The VLDL remnant particle with less TG is LDL.
33
LDL is known as?
LDL is known as he bad cholesterol because it can be taken up by macrophages in the arterial wall and pose the risk for atherosclerosis.
34
Endogenous lipid and reverse cholesterol transport - HDL?
HDL contains a lot of protein and takes cholesterol back to the liver. - The protein part of HDL is secreted by the liver complexed with some phospholipids. Macrophages and peripheral tissues secrete cholesterol to these particles to form HDL.
35
What is HDL known as?
HDL is known as the "good cholesterol" because it removes fat from the periphery and transports it back to the liver.
36
What is rthe role of chylomicrons?
Chylomicrons transport TAGs from intestines to adipose and other tissues. After TAGs are taken up by adipose tissue, the remaining lipoprotein particle (= chylomicron remnant) is taken up by the liver.
37
What is the role of VLDL?
Very-low-density lipoproteins transport TAGs from the liver to adipose and other tissues. After TAGs are taken up by the adipose tissue, the remaining lipoproteins have mostly cholesterol and are low density lipoproteins (= LDL).
38
Peripheral tissue can take up...?
Peripheral tissue can take up low-density lipoproteins to get cholesterol. LDL not taken up by peripheral tissues are cleared by the liver. When LDL levels are too high, LDL can deposit cholesterol in macrophages in the arterial wall (bad cholesterol).
39
What is the role of HDL?
High-density lipoproteins transport cholesterol from the tissues to the liver. The liver excretes (gets rid of) cholesterol into bile and the intestine. High HDL levels counteract the cholesterol deposition by LDL.
40
Good and bad cholesterol?
LDL = bad cholesterol and increases risk of cardiovascular disease and atherosclerotic disease HDL is the good cholesterol! It counteracts the affects of LDL
41
The levels of which lipoprotein class do you expect to be increased in the circulation after a greasy fast-food lunch? A) Very low-density lipoproteins B) High density lipoproteins C) Chylomicrons D) Low density lipoproteins E) None
C) Chylomicrons
42
What is white adipose tissue specialized for?
White fat is specialized for the storage of TAGs (as opposed to brown fat: non-shivering thermogenesis)
43
Distinct appearance of white adipocytes?
White adipocytes have a distinct appearance: large, central lipid vacuoles that take up much of the intracellular space
44
TAG can be released from white adipocytes?
TAG from droplets in white adipocytes can be released for use in other tissues.
45
Wjere are nuclei ocated in white adipocytes?
Nuclei are peripherally located, and the cytoplasm forms a thin peripheral ring around the central vacuole
46
How large can white adipocytes grow?
White adipocytes can grow up to 100 μm in diameter and are one of the larger cells in the human body
47
Storage of dietary or liver-derived fat in adipocytes (3 methods)?
1. Hydrolysis of TAGs in lipoproteins 2. Uptake of fatty acids and then 3. Re-synthesis of TAGs
48
How are fatty acids activated and what are Fatty-acyl-CoA esterified to?
Fatty acids are activated with CoA * Fatty-acyl-CoA are esterified with glycerol-3-phosphate to TAGs
49
What does fat catabolism begin with?
Fat catabolism typically begins with triacylglycerol.
50
What are TAGs converted into?
TAGs in adipose tissue are converted into free fatty acids in response to hormonal signals.
51
What are the five steps in converting TAG into free fatty acids?
1. Hormones activate protein kinase A through the cAMP cascade. (adenylyl cyclase) 2. Protein kinase A phosphorylates perilipin, resulting in the restructuring of the lipid droplet and release of the coactivator of ATGL, thereby activating ATGL. 3. ATGL converts TAG into diacylglycerol. 4. Hormone-sensitive lipase releases a fatty acid from diacylglycerol, generating monoacylglycerol. 5. Monoacylglycerol lipase completes the mobilization process
52
when are these hormonal signals sent?
Hormonal signals are made when we are stressed, fasting or during catecholamine release. - This is when peripheral tissues need more fatty acids for ATP production.
53
What is the result of mobilizing stored TAG
Per TAG, we would get 3 free fatty acids and a glycerol. - This occurs in the adipocytes.
54
What are the 6 steps needed to use or burn (oxidize) fatty acids?
1. Activation of fatty acid required for entry into mitochondria 2. Translocation from cytosol to mitochondria 3. 1st Oxidation 4. Hydration 5. 2nd Oxidation 6. Thiolysis Note: latter four are part of B-oxidation.
55
Where can fatty acids be broken down?
Fatty acids can be broken down by nearly any tissue except the brain and red blood cells.
56
Step one - activation of fatty acid?
Upon entering the cell cytoplasm, fatty acids are activated by attachment to coenzyme A. * Catalyzed by acyl CoA synthetase
57
What is step one driven by?
Step one is driven by the hydrolysis or PPi
58
What is the cost equivalent of step one?
Cost equivalent to 2 ATP
59
What is the consequence of step one?
Once the large and polar coenzyme A is attached, the fatty acid is unable to diffuse back across the membrane and remains inside the cell to be metabolized.
60
What is step 2 of the process?
Activated fatty acids can cross the outer mitochondrial membrane through the voltage-dependent ion channels, also called porin channels. * To cross the inner mitochondrial membrane: we need carnitine.
61
What is the use of acyl carnitine translocase for step 2?
The entry of acyl carnitine into the mitochondrial matrix is mediated by a translocase. Carnitine returns to the cytoplasmic side of the inner mitochondrial membrane in exchange for acyl carnitine
62
What is the transport step (2) regulated by?
Transport step of fatty acids into mitochondria is regulated.
63
What slows down atty acid oxidation?
Carnitine deficiency slows down fatty acid oxidation
64
3rd step of fatty acid utilization?
this is the 1st oxidation by Acyl-CoA dehydrogenase: The first reaction in each round of degradation is the oxidation of acyl CoA by an acyl CoA dehydrogenase to produce an enoyl CoA with a trans double bond between C-2 and C-3
65
WHat is the electron acceptor in step 3?
As in the dehydrogenation of succinate in the citric acid cycle, FAD rather than NAD+ is the electron acceptor because the ΔG for this reaction is insufficient to drive the reduction of NAD+
66
Additionally, what occurs with Ubiquinone during step 3?
Ubiquinone is then reduced to ubiquinol, which delivers its electrons to the second proton- pumping site of the respiratory chain.
67
What is the resulting ATP production from the dehydrogenation step (3)?
Like the oxidation of succinate to fumarate, 1.5 molecules of ATP are generated per molecule of FADH2 formed in this dehydrogenation step.
68
What is step four in fatty acid utilization?
The next step is the hydration (uses water) of the double bond between C-2 and C-3 by enoyl CoA hydratase.
69
Step four is stereospecific?
The hydration of enoyl CoA is stereospecific. Only the L isomer of 3-hydroxyacyl CoA is formed when the trans-Δ2 double bond is hydrated. (The enzyme also hydrates a cis-Δ2 double bond, but the product then is the D isomer.)
70
What is the fifth step in fatty acid utilization?
The hydroxyl group at C-3 is converted (oxidized) into a keto group and NADH is generated. * This oxidation is catalyzed by L-3-hydroxyacyl CoA dehydrogenase, which is specific for the L isomer of the hydroxyacyl substrate
71
What is the sixth step in fatty acid utilization?
The final step is the cleavage of 3-ketoacyl CoA by the thiol group of a second molecule of coenzyme A, which yields acetyl CoA and an acyl CoA shortened by two carbon atoms. * This thiolytic cleavage is catalyzed by β-ketothiolase.
72
what happens to the shortened acyl CoA?
* The shortened acyl CoA then undergoes another cycle of oxidation, starting with the reaction catalyzed by acyl CoA dehydrogenase.
73
Where are acyl units lost from?
acetyl units are not lost from the methyl end of the fatty acid but from the activated, CoA end.
74
How is B-oxidation regulated?
β-oxidation is regulated primarily by the availability of free CoA (to make acyl-CoA) and by the ratios of NAD+/NADH and Q/QH2 (these reflect the state of the oxidative phosphorylation system).
75
How are the enzymes of B-oxidation subject to product inhibition?
most of the enzymes of β-oxidation are subject to product inhibition. Ketoacyl-CoA, the product of the pathways’ third reaction, also inhibits the enzymes that catalyze the first two reactions
76
Oxidation of odd chain fatty acid: heptadecanoic acid (C17:0)?
Heptadecanoic acid, C17:0, occurs as a trace component of the fat and milkfat of ruminates. * Odd-chain fatty acids yield propionyl CoA in the final thiolysis step. * The activated three-carbon unit in propionyl CoA enters the citric acid cycle after it has been converted (via carboxylation) into succinyl CoA (at the expense of the hydrolysis of 1 ATP).
77
How can part of a fatty acid be glucogenic?
Production of propionyl CoA, through conversion to succinyl CoA > oxaloacetate, is the only way that part of a fatty acid can be glucogenic
78
Oxidation of very long fatty acid chains (> 20)
Oxidation in peroxisomes to medium-chain fatty acids, which are then oxidized in mitochondria. - Different 1st step, acyl CoA oxidase. - Note: Electrons removed from the acyl-CoA are transferred not to Q but directly to O2 to produce H2O2. - Genetic defects in peroxisomal transporters means a build-up of very long chained fatty acids.
79
Unsaturated fatty acid oxidation?
Additional enzymes such as isomerases and reductases degrade the carbon chain around double bonds. - Energy yield is lower than from saturated fatty acids
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