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Medical Biochemistry and Pathophysiology > Week 3A: Fatty acid metabolism and Membrane lipids > Flashcards

Week 3A: Fatty acid metabolism and Membrane lipids Flashcards

-HC -WC -Chapter 22 -Chapter 27

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USMLE® Step 1 flashcards
1
Q

Functions fatty acids

A

-Building blocks of phospholipids in cell membranes
-Targeting: bind proteins, directing them to designated locations in membranes
-Messengers: FA derivatives serve as hormones or messenger molecules like diacylglycerol (DAG)
-Energy: storage as triacylglycerols (TAGs)

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2
Q

Which bonds links FAs and glycerol in TAGs?

A

ester bonds
> condensation of hydroxylic and carboxylic group

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3
Q

Why are TAGs called neutral fats

A

Neutral charge
> free fatty acids are charged

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4
Q

High concentrations of DAG are correlated to..

A

defect in lipid degradation

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5
Q

How is the FA precursor of the hormones prostaglandins called?

A

Arachidonic acid

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6
Q

Type of chains found in fatty acids

A

acyl chains

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7
Q

Why do FAs yield much energy compared to proteins and carbohydrates?

A

They are strongly reduced

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8
Q

What is the natural polarity and hydro state of FAs?

A

Nonpolar and hydrophobic, forms hydrophobic interactions

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9
Q

Where are TAGs stored in the cell (which special organelle)

A

Fat droplets: dense in energy

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10
Q

Fats are stored anhydrous, what does this mean?

A

Water free

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11
Q

Why are fats dense in energy

A

They do not bind water and therefore weigh less per energy output

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12
Q

FAs do not have hydrogen acceptors. What are hydrogen bond acceptors? What about TAGs?

A

Free O group.
> The ester bonds of TAGs contain hydrogen bond acceptors and bind a bit of water

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13
Q

How does the unilocular lipid droplet in adipocytes develop?

A

Little droplets fuse to one with hydrophobic interactions

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14
Q

Adipocytes store …, when the lipid droplet grows, there is ….

A

TAGs, hypertrophy of the adipocyte

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15
Q

How is the function of the pancreas to secrete lipases into the GI tract called?

A

Exogeneous function

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16
Q

Uptake TAGs from food

A

-TAGs + H2O -> FAs + MAGs (by pancreatic lipase)
- Import into mucosal cell / enterocyte
- Make TAGs from FAs and MAGs
- Form chylomicrons (lipoproteins)
- To lymphatics
- To blood
-To adipose tissue and muscle using LPL (lipoprotein lipase, digests chylomicron to 3 FAs and glycerol, uptake FAs by target cell)

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17
Q

Pancreatic lipase has a lot of activity but limited operation rate, explain

A

It removes the outer fatty acids of TAG but cannot reach the middle one, products are 2 FAs and 1 MAG.

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18
Q

Why are proteins added to the lipids to make chylomicrons?

A

To make them water soluble for transport in blood

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19
Q

Where does LPL operate

A

LPL is secreted by organs which need the FAs, like muscle cells and adipocyes

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20
Q

What happens to fats stored in adipocytes in the fasted state?

A

They are taken for mobilization of energy

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21
Q

Three global steps of burning fat: lipolysis and beta-oxidation

A
  1. Mobilization
    -Breakdown TAGs in adipocytes into glycerol and FAs > transport to other tissues using carrier
  2. Activation and transport
    -Activation FAs (stay inside cell, charge, and to get more energy, destabilization) > transport into mitochondrial matrix for degradation
  3. Degradation: FAs are broken down into acetyl-CoA in step-by-step manner > acetyl-CoA is oxidized in TCA cycle to CO2 and H2), generating high energy electrons on carriers for respiratory chain and ATP synthesis
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22
Q

Which enzyme of the fasted state promotes TAG breakdown?

A

Glucagon

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23
Q

Where is fat stored?

A

In adipocytes and muscle

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24
Q

Which central enzyme has a role in TAG breakdown in adipocytes and muscle cells? How is it activated?

A

PKA
Activation:
> Glucagon/epinephrine binds to 7TM receptor
> Activation Gas –> activation adenylate cyclase
> Conversion ATP to cAMP
> cAMP binds regulatory subunits PKA: activation

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25
Q

How does PKA induce TAG breakdown / lipolysis

A

-PKA activates perilipin and hormone sensitive lipase (HS lipase)
-Perilipin-P adds CA to ATGL > ATGL catalyzes TAG to DAG with FA
-HS lipase-P catalyzes DAG to MAG and FA
-MAG lipase catalyzes MAG to glycerol and FA

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26
Q

How is glycerol used when TAGs are broken down?

A

Glycerol is a precursor of gluconeogenesis for the liver in the fasted state
> or glycolysis to generate pyruvate

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27
Q

Released FAs after lipolysis are used for…

A

energy > transport to blood

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28
Q

Main human FA

A

Palmitate (C16)
> also product of FA synthesis

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29
Q

Unsaturated FAs contain…

A

double bonds

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30
Q

Fats in human mainly consist … double bonds

A

cis

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31
Q

Oleate is a C18, unsaturated, cis omega-9 FA. How is this determined?

A

From the omega carbon (last counted from carboxylic end), count backwards until double bond.

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32
Q

Numbered carbon counts in FAs

A

Count from carboxylic end, and include the carbolic acid carbon

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33
Q

Greek letters carbons counting in FAs

A

Count from carboxylic end but do not include the carboxylic acid carbon

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34
Q

Which carbon is oxidated in FA breakdown?

A

Beta carbon > beta-oxidation

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35
Q

Which greek letter indicates a double bond in numbered nomenclature

A

the delta triangle
> use cis or trans

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36
Q

Trans unsaturated fats are uncommon and usually…

A

not so good

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37
Q

Which abundant C20 FA do we have?

A

Arachidonate, unsaturated, made in our body to make prostaglandins after conversion to arachidonic acid (arachidonate is the base/alkaline form)

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38
Q

FAs are insoluble, how do they travel through blood?

A

Bound to serum albumin (abundant plasma protein)

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39
Q

The reaction of FA binding to albumin is a … reaction

A

equilibrium

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40
Q

How does the FA bind to serum albumin

A

to the hydrophobic pocket

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41
Q

How are FAs taken up by target cells?

A

The cells express FA uptake transporters

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42
Q

Do all FAs strictly need transporters for import?

A

No, very small FAs can wiggle and diffuse through the PM, long ones need help

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43
Q

Which membrane transporters transport long-chain FAs over the PM?

A

FATP and CD36
> FATP: Fatty acid transport protein.

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44
Q

Activation step inside target cell to retain FAs

A

Add a CoA with thioester bond (high energy)
> make acyl-CoA

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45
Q

CoA is a carrier of …

A

carbons

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46
Q

Net reaction and ATP costs FA activation

A

FA-COO- + CoA-HS + ATP <=> AMP + PPi + acyl-CoA (acyl-C=O-S-CoA)
> it costs 2 ATP to regenerate ATP from AMP
> acyl-CoA synthetase

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47
Q

Intermediate made in FA activation

A

acyl-adenylate
-addition of AMP to fatty acid carboxyl end using ATP> AMP
-energy used to switch AMP to S-CoA (thioester bond) + AMP

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48
Q

When is fatty acid breakdown (beta-oxidation) committed?

A

When the FA is transported to the mitochondrial matrix (past the inner mitochondrial membrane)

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49
Q

Can FAs pass the outer mitochondrial membrane without energy use?

A

Yes, through a gradient.

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50
Q

Which FAs require a special transport mechanism to pass the inner membrane of mitochondria?

A

Long-chain FAs (12-20 C)

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51
Q

To which molecule is the acyl group transferred to tranfer across the inner membrane. Which enzyme is involved in the committed step?

A

To carnitine, enzyme: carnitine palmitoyl transferase 1 (CPT-1)

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52
Q

How is acyl-carnitine flipped over the inner membrane and what happens next?

A

A translocase transfers the molecule. In the matrix CPT-2 transfers the acyl group back to a CoA to form acyl-CoA

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53
Q

CPT-1 is the committed step in ..

A

beta-oxidation

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54
Q

Which process will acyl-CoA enter in the matrix?

A

The beta-oxidation cycle

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55
Q

Reaction sequence beta-oxidation cycle

A

Oxidation (generate FADH2)
Hydration
Oxidation (generate NADH+H)
Thiolysis

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56
Q

End products one beta-oxidation cycle

A

acetyl-CoA (C2) + acyl-CoA (Cn-2)

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57
Q

FAD is the electron acceptor in the first oxidation step of the beta-oxidation cycle. What happens to it?

A

Transfer to Coenzyme Q in inner membrane which transfers the electrons to complex 3 of the respiratory chain

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58
Q

First oxidation step b-oxidation cycle

A

Acyl-CoA + FAD > trans-delta2-enoyl-CoA + FADH2 (double bond at C2-C3, release 2 H)
Enzyme: acyl-CoA dehydrogenase

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59
Q

Isozymes acyl-CoA dehydrogenase

A

-LCAD: long chain
-MCAD: medium chain
-SCAD: short chain

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60
Q

Hydration in b-oxi cycle

A

Trans-delta2-enoyl-CoA + H2O > L-3-hydroxyacyl-CoA (addition OH group at C3 and extra H group at C2, counting from carboxylic end connected to CoA)
-Stereospecific reaction
-Enzyme: enoyl-CoA hydratase

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61
Q

Oxidation 2 in b-oxi cycle

A

NAD+ as electron acceptor
-Enzyme specific for L-isomer: L-3-hydroxyacyl-CoA dehydrogeanase
-L-3-hydroxyacyl-CoA + NAD+ > 3-ketoacyl-CoA + NADH + H+

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62
Q

Thiolysis in b-oxi cycle

A

-3-Ketoacyl-CoA + HS-CoA > Acyl-CoA + Acetyl-CoA
-Enzyme: Thiolase ( beta-ketothiolase)

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63
Q

Range of fatty acids with site of catabolism and membrane transport

A

-Short chain (C2-4), Mitochondrion, Diffusion
-Medium (C4-12), Mitochondrion, Diffusion
-Long (C12-20), Mitochondrion, Carnitine cycle
-Very-long (C20+), Peroxisome, Carnitine cycle (export)

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64
Q

Palmitate is a … (range) FA

A

Long-chain (C16 is within 12-20)

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65
Q

Peroxisomes, unlinke mitochondria, lack the …

A

electron transport chain

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66
Q

How does the peroxisome take care of released electrons in oxidation of very-long FAs?

A

Oxygen is used as electron acceptor
> Acyl-CoA dehydrogenase has FADH2 bound in reducted state, this is oxidized by reducing O2 to H2O2 (hydrogen peroxide)
-H2O2 is converted to H2O and 0.5 O2 by enzyme Catalase.

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67
Q

What happens to the remainder of the reactions beside the first oxidation in peroxisomes?

A

They are the same as in the mitochondria but performed in the peroxisomes.
> Shortened until medium chain or long chain FAs and then transported to mitochondria for further degradation.

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68
Q

What happens to the formed acetyl-CoA and NADH in peroxisomes?

A

Peroxisomes do not have a TCA cycle, the acetyl-CoA and NADH is transported to mitochondria and degraded to CO2 and H2O there.

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69
Q

How many beta-oxidation cycles for palmitate (C16)?

A

7 cycles
16/2 = 8 but the last cycle yields two acetyl-CoA (C2)

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70
Q

Degradation odd numbered carbons (FAs)

A

Make propionyl-CoA (C3) and acetyl-CoA (C2) out of 3-ketopentanoyl-CoA (C5) in the final thiolysis step.
> with the C3 you can make glucose, with the C2 you cannot
> C3: intermediate TCA cycle made: anaplerosis. Succinyl CoA which can be converterted to oxaloacetate

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71
Q

Propionyl-CoA conversion to make glucose

A

Propionyl-CoA > Succinyl-CoA (intermediate TCA cycle) > Oxaloacetate > Gluconeogenesis in liver

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72
Q

Which fats can be used to make glucose?

A

Odd numbered, done in the mitochondria.

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73
Q

Additional enzymes for breakdown unsaturated FAs

A

-For degradation double bond on odd-carbon: isomerase (enoyl-CoA isomerase) needed to shift position double bond
-Degradation double bond on even-carbon: both isomerase and reductase (dienoyl-CoA reductase) required.
> Only these two needed additionally for complete degration of (poly)unsaturated fatty acids

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74
Q

Ketone body synthesis substrate

A

Acetyl-CoA

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75
Q

Ketone body synthesis organ

A

The liver, in mitochondrial matrix

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76
Q

When ketone body synthesis

A

When fat breakdown predominates: long fasting

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77
Q

Committed step enzyme in ketogenesis

A

HMG-CoA synthase

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78
Q

Reactions ketogenesis

A

2 acetyl-CoA (from beta-oxidation) <=> acetoacetyl-CoA (C4) + CoA
Acetoacetyl-CoA + Acetyl-CoA (C2) <=> HMG-CoA (C6) (HMG-CoA synthase, committed step)
HMG-CoA > acetoacetate (C4) + Acetyl-CoA (C2)
(Acetoacetate + NADH + H+ <=> D-3 hydroxybutyrate (C4) + NAD+)
(Spontaneous: Acetoacetate > Acetone (C3) + CO2)

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79
Q

The two ketone bodies

A

-Acetoacetate
-D-3-hydroxybutyrate: more reduced, more energy carried, NADH needed for synthesis from acetoacetate.

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80
Q

Cell is very reduced > Lots of NADH > more of this ketone body:

A

d-3-hydroxybutyrate

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81
Q

Acetoacetate is instable: explain

A

It can spontaneously be converted to acetone which releases CO2
> decarboxylation
> fruity scent: smelled when diabetes: acetone is a gas and is released in breath

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82
Q

Ketone body breakdown (for which organs)

A

Fuel for heart, muscle and brain in starvation

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83
Q

Acetoacetate breakdown (ketone body)

A

Acetoacetate + succinyl-CoA (intermediate TCA cycle, cataplerosis) > acetoacetyl-CoA + succinate (by enzyme CoA transferase)
Acetoacetyl-CoA + CoA > 2 acetyl-CoA (by enzyme thiolase)

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84
Q

How is excess acetyl-CoA shipped to the brain and other organs during starvation?

A

Through ketone bodies made by the liver
> liver does not have the transferase and cannot use ketone bodies to make acetyl-CoA (it has enough)
> brain can do without glucose for longer by using ketone bodies (1-2 weeks)

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85
Q

Liver provides ketone bodies to the peripheral tissue during two states:

A

Fasted and starvation state

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86
Q

HC16: Fatty acid synthesis cycle

A

Condesation
Reduction
Dehydration
Reduction
> reverse of beta-oxidation cycle

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87
Q

Where in the cell does FA synthesis occur?

A

In the cytosol

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88
Q

In FA degradation, the acyl carrier is the SH group of CoA. In FA synthesis, this is the … group of …

A

SH group of acyl-carrier protein (ACP)
> thioester bond

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89
Q

Activation of acetyl-CoA for FA synthesis

A

Acetyl-CoA (C2) > Malonyl-CoA (C3) (the activated C2 donor, used to extent FA chains)
(adding a carbon: carboxylation, using HCO3-)

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90
Q

Which electron carrier is required in FA synthesis. And which carriers are made in the breakdown?

A

NADPH used in synthesis
NADH and FADH2 made in breakdown

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91
Q

Making Palmitate from 8 Acetyl-CoA costs …

A

7 ATP and 14 NADPH

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92
Q

How are acetyl groups transferred to the cytosol?

A

It is transferred to citrate (C6) in TCA cycle and citrate in the cytosol can be converted to acetyl-CoA

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93
Q

Committed step FA synthesis with enzyme

A

Acetyl-CoA + ATP + HCO3- > Malonyl-CoA + ADP + Pi + H+
(enzyme: acetyl-CoA carboxylase)
> the rate limiting step

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94
Q

Prosthetic group of Acetyl-CoA carboxylase

A

Biotin (vitamin B7)

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95
Q

Which enzyme also has biotin as prosthetic group?

A

Pyruvate carboxylase

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96
Q

What is the biotin able to bind? What does acetyl-CoA carboxylase facilitate?

A

Activated CO2 (carboxyphosphate)
> acetyl-CoA carboxylase transfers CO2 group from carboxybiotin to acetyl-CoA, resulting in malonyl-CoA
> irreversible, committed, rate-limiting

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97
Q

Function acetyl-CoA carboxylase is similar to…

A

carboxylation of pyruvate to form oxaloacetate by pyruvate carboxylase in the gluconeogenesis

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98
Q

The thiol (SH) group of ACP is a part of the … group

A

Phosphopantetheine group (end in =O)

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99
Q

Which enzyme complex catalyzes the FA synthesis (elongation)

A

Fatty acid synthase complex
> individual proteins fused to one polypeptide in eukaryotes

100
Q

Starting reactions of elongation phase FA synthesis

A

Formation acetyl-ACP and malonyl-ACP
-Acetyl/Malonyl-CoA + ACP > A/M-ACP + CoA
Enzymes: acetyl/malonyl transacylase

101
Q

First step FA synthesis (remember, cycle opposites)

A

Condensation:
Acetyl-ACP (C2) + Malonyl-ACP (C3) > Acetoacetyl-ACP (C4) + CO2 (carbon from activation!) + ACP

102
Q

Why is the condensation reaction of FA synthesis in a favorable equilibrium? Why is the reaction driven by ATP nevertheless?

A

Because the decarboxylation of malonyl-ACP contributes to the reduction of Gibbs free energy (negative).
The reaction is driven by ATP which was used to carboxylate acetyl-CoA to malonyl-CoA.

103
Q

Elongation phase FA synthesis after condensation

A

Reduction>Dehydration>Reduction
-reduction keto group (C=O) of C3 carbon to methylene (CH2) group (count from carboxyl group linked to ACP)
-NADPH supplies reduction equivalents (electrons)
-Acetoacetyl-ACP + NADPH > d-3-hydroxbutyryl-ACP + NADP+
> Crotonyl-ACP + H2O
Crotonyl-ACP + NADPH > Butyryl-ACP + NADP+

104
Q

Second round of elongation phase

A

Butyryl-ACP is extended by two carbon atoms derived from Malonyl-ACP (during condensation, one C is lost into CO2)

105
Q

When does the chain extension stop for FA synthesis?

A

At C16: palmitate

106
Q

Ruler enzyme of the chain length

A

Thioesterase
> hydrolyzes the thioester bond between ACP and the FA.

107
Q

The human fatty acid synthase complex is one polypeptide chain with one active site, of:

A

Malonyl-acetyl transacylase
> this catalyzes the addition of ACP to both the groups of acetyl-CoA and malonyl-CoA.

108
Q

For the human fatty acid synthase to work, … is essential

A

dimerization

109
Q

How many acetyl-CoA make palmitate

A

8 (C2) make 1 (C16)

110
Q

When are FAs made?

A

In fed state > insulin, enough energy, good times

111
Q

Complete sum reaction acetyl-CoA to palmitate

A

8 acetyl-CoA + 7 ATP + 14 NADPH + 6 H+ >
palmitate + 14 NADP+ + 8 CoA + 6 H2O + 7 ATP + 7 Pi

112
Q

In which state does the FA synthesis occur?

A

When insulin rules, in the fed, energy-rich state

113
Q

How is the acetyl-CoA transported to the cytosol, where FA synthesis takes place?

A

Using citrate.
In mitochondrion:
-Acetyl-CoA condenses with oxaloacetate to citrate (citrate synthase)
-Citrate moves through transporters or channels to the cytosol.
-There: citrate splits into acetyl-CoA and oxaloacetate (ATP-citrate lyase)

114
Q

Redirecting oxaloacetate from cytosol to mitochondrion after acetyl-CoA shuttling

A

in cytosol
-Oxaloacetate + NADH > malate + NAD+ (malate dehydrogenase)
-Malate + NADP+ > Pyruvate + NADPH (malic enzyme)
-transport to mitochondrion of pyruvate
-Pyruvate > oxaloacetate (pyruvate carboxylase)

115
Q

For each acetyl-CoA transferred to the cytosol … NADPH is generated

A

1

116
Q

Oxidative phase of the PPP (glucose-6-P>ribulose-5-P) yields ….

A

2 NADPH and releases CO2

117
Q

The two fates of pyruvate in mitochondrion

A

-To acetyl-CoA (in fed state, by pyruvate dehydrogenase)
-To oxaloacetate (in fasted state, gluconeogenesis for example, by pyruvate carboxylase)

118
Q

End product FA synthesis: palmitate (C16). How are long-chain and very-long chain fatty acids with >C16 made?

A

Elongation of palmitate with C2 units (activated C2 donor: malonyl-CoA/ACP)
> these reactions take place on the cytoplasmic face of the ER and are catalyzed by fatty-acid elongase

119
Q

How are unsaturated fatty acids made?

A

Takes place on the ER cytoplasmic side, catalyzed by fatty-acid desaturase
> requirement of O2 and NADH(/NADPH)

120
Q

Which omega unsaturated fatty acids can be made in the human cell?

A

Omega-9
> NOT omega-3/6

121
Q

Which important omega fatty acids cannot be synthesized by humans?

A

LA (omega-6)
ALA (omega-3)
EPA (omega-3)
DHA (omega-3)

122
Q

omega-3/6 fatty acids are called

A

essential fatty acids > uptake by diet

123
Q

Concern essential fatty acids for vegans

A

ALA is from plants, EPA and DHA from algae eating fatty fish
> conversion ALA to EPA and DHA is slow

124
Q

LA (linoleic acid) and a-linolenic acid (ALA) serve as precursors for a large number of unsaturated fatty acids, among which the substrate for prostaglandin H2 synthase: ??

A

arachidonic acid

125
Q

Why is the slow conversion of ALA to other essential omega-3 FAs a problem?

A

Needed in the brain

126
Q

when the pKa is lower than the pH, then the ..

A

base/alkaline is made more

127
Q

In humans, more arachidonic acid or arachidonate?

A

More arachidonate: pKa=4.8

128
Q

Arachidonic acid is an important precursor for synthesis of ….

A

eicosanoids (C20)
> hormones which act locally

129
Q

Arachidonate can be converted to the eicosanoid prostaglandin H2, which can be converted to other prostaglandins. Name all enzymes, and inhibitors

A

Prostaglandin H2 synthase makes prostaglandin H2 (inhibited by aspirin and ibuprofen: broad action: all prostaglandins inhibited)
> Prostaglandin H2 can be converted to prostacyclin or thromboxanes or others by their synthases

130
Q

Effects prostaglandins

A

-Stimulate inflammation
-Regulate blood flow to organs
-Modulate ion transport across membranes

131
Q

How is the enzyme (which) in the committed step of FA synthesis regulated?

A

Acetyl-CoA carboxylase (ACC, for acetyl-CoA> malonyl-CoA) is regulated through hormones (kinases) and allosteric regulators

132
Q

Phosphorylation regulation of ACC

A

-ACC is inactivated by phosphorylatoin by AMPK, AMP-dependent kinase, a sensor of energy status (low energy activated) > the phosphorylation costs ATP as well!
-ACC is activated by dephosphorylation by protein phosphatase 2A (PP2A)

133
Q

Allosteric regulation ACC

A

-Positive: citrate (enough energy, TCA cycle halted, accumulation, fed state)
-Negative: palmitoyl-CoA (product inhibition, only in FA breakdown: reciprocal regulation)

134
Q

How are citrate concentrations high when the energy status of the cell is high?

A

High concentration ATP and NADH because Electron transport chain is halted.
> conversion isocitrate to a-ketoglutarate (by ATP and NADH, pos by ADP) and that to succinyl-CoA are inhibited (ATP, succinyl-CoA and NADH)

135
Q

Without activation, the conformation of ACC is?

A

In dimers, but the ACC is only active when activated by citrate, which promotes the polymerization enzyme for ACC. ACC is only active as a polymer. (ACC filaments)

136
Q

Hormonal regulation of ACC

A

Glucagon and adrenaline promote AMPK.
Insulin promotes PP2A

137
Q

Reciprocal regulation fatty acid metabolism

A

-Palmitoyl (acyl)-CoA (degradation intermediate) inhibits ACC (synthesis committed step)
-Malonyl-CoA (committed intermediate synthesis) inhibits CPT-1 (commited step enzyme beta-oxidation/FA breakdown)

138
Q

MCAD deficiency

A

Deficiency Medium-chain acyl-CoA dehydrogenase (first step beta-oxidation cycle)
> not enough glucose made
> acetyl-CoA not formed anymore when C10 FAs are formed after few beta-oxidation cycles of palimitoyl(C16)-CoA.
> accumulation Medium chain acyl-CoA esters
> Acetyl-CoA cannot be made, all CoA occupied, no activation of pyruvate carboxylase by acetyl-CoA, no glucogenesis
> no substrate ketogenesis (important source of energy for brains of small children

139
Q

HC17: For membranes to function, membrane lipids need to move freely, so what is essential

A

The polar hydrophilic side

140
Q

Types of membrane lipids: structure phospholipids

A

Glycerol with 2 ester bound FAs and a polar head group

141
Q

Why are TAGs not found in membranes?

A

No polar head group
> same synthesis pathway as phospholipids

142
Q

What is the main intermediate in the phospholipid/TAG synthesis

A

Phosphatidate/ diacylglycerol-3-P (DAG-3-P)

143
Q

Synthesis TAGs and phospholipids pathway

A

Glucose is converted to glycerol-3-phosphate through DHAP (intermediate)
or: TAGs from adipocytes or diet is split into glycerol and FFAs and the glycerol gets a Pi added to become glycerol-3-P.
>In the ER: Conversion glycerol-3-P to Phosphatidate (DAG-3-P) adding 2 FAs
>Phosphatedate/DAG-3-P can be converted to TAG in the liver by adding FFAs
> Phosphatidase/DAG-3-P can be converted to phospholipids by condensing with an alcohol, by first activating one of the two with a NTP like ATP.

144
Q

Three important phospholipids

A

-Phosphatidyl choline (PC)
-Phosphatidyl ethanolamine (PE)
-Phosphatidyl serine (PS)

145
Q

Phospholipids differ in function by different …

A

head groups

146
Q

Synthesis PE and PC

A

Both through a pathway from ethanolaine/choline using CTP-activated intermediates and diacylglycerol (DAG) addition.

147
Q

From PE to PC or PS

A

PE > PC by PE-methyltransferase
PE/PC > PS

148
Q

In which leaflet of lipid bilayer is PS present?

A

Intracellular laeflet

149
Q

What happens if PS accidentally appears in the outer leaflet of the PM?

A

Flippase flips it back to the inner leaflet

150
Q

What if flippase is blocked?

A

PS appears on extracellular leaflet: induces apoptosis

151
Q

Where are PE and PC naturally found in the membrane?

A

PE inner leaflet (intracellular) and PC outer leaflet.

152
Q

Which phospholipid has an important role in signal transduction

A

Phosphatidyl inositol
> Phosphorylated to PIP, PIP2 or PIP3.

153
Q

Which enzyme cleaves PIP2? What are the signal transduction products?

A

Phospholipase C
> creates membrane bound DAG and free IP3

154
Q

Outside the cell, … bind the transmembrane proteins

A

sugar chains

155
Q

Structure of cardiolipin

A

Polar heads attached to each other (2)

156
Q

What process is promoted by cardiolipin (CL)?

A

The curvature of the inner mitochondrial membrane > proper oxidative phosphorylation

157
Q

Defect cardiolipin effect

A

No curvature inner mitochondrial membrane
> complexes of electron transport chain do not get together > no proper oxidative phosphorylation and ATP synthesis

158
Q

Sphingolipids structure

A

Backbone of ceramide with a OH group of his backbone as polar head.
> The ceramide already contains a FA bound to its backbone with a peptide bond (amino acid with a FA bound to N terminus and OH as R group)
> can bind 1 FA at carboxyl end

159
Q

Synthesis ceramide

A

Palmitoyl-CoA (FA) + serine (amino acid) > ceramide.

160
Q

Synthesis sphingomyelin and function and pathology

A

Ceramide + PC > Sphingomyelin + DAG
(addition PC to the OH group
- important for nerve function and insulation (impulse transduction)
- Defect: MS, Niemann-Pick

161
Q

Ceramide is also a substrate to make cerebroside, how?

A

Ceramide + UDP-glucose > cerebroside + UDP (glucose added to OH R-group of the ceramide)

162
Q

Synthesis ganglioside

A

Addition of activated sugars to glycosphingolipids like cerebroside
> sphingolipids with oligosaccharide chain

163
Q

Many lysosomal storage disordered are through…

A

defect of enzyme in sphingolipid metabolism

164
Q

Functions cholesterol

A

-Membrane flexibility
-Bile acids
-Hormones

165
Q

Cholesterol synthesis

A

-Acetyl-CoA + Acetoacetyl-CoA + H2O > HMG-CoA + CoA (HMG-CoA synthase)
-HMG-CoA + 2 NADPH + 2H+ > mevalonate + 2 NADP+ + CoA (HMG-CoA reductase)

166
Q

Committed step cholesterol synthesis

A

By HMG-CoA reductase
(HMG-CoA > Mevalonate)
> costs a lot of energy: 2 NADPH

167
Q

Which molecules inhibit HMG-CoA reductase and how

A

Statins like lovastatin competitively bind for the HMG group in HMG-CoA reductase. (resemble the structure)

168
Q

Besides cholesterol, HMG-CoA has another fate. Which?

A

In mitochondria:
HMG-CoA > acetyl-CoA and acetoacetate (ketone body: for energy)

169
Q

Mevalonate > Cholesterol

A

Mevalonate (C6) > Isopentenyl pyrophosphate (C5)
3xC5 > C15
2xC15 > C30 (squalene, by squalene synthase)
Squalene > lanosterol (ring formation)
Lanosterol > Cholesterol (C27, three methyl groups removed, two methyl group together on outer ring and the ring directed methyl group in the third outer ring)

170
Q

Which transcription factor is activated when there is much cholesterol in the cell? What are the effects?

A

LXR
> Less uptake cholesterol
> Promote cholesterol efflux
> Inhibit cholesterol synthesis

171
Q

Which transcription factor is active when there is little cholesterol in the cell and what are the effects?

A

SREBP
> More uptake cholesterol
> Inhibit cholesterol efflux
> Promote cholesterol synthesis

172
Q

How is LXR activated

A

LXR binds to target DNA
> cholesterol levels increase
> Oxy-sterols bind to LXR > go into nucleus > find target genes and inhibit pathways for cholesterol synthesis

173
Q

Which gene is activated by LXR?

A

ABCA1, for cholesterol efflux

174
Q

Transcriptional regulation SREBP

A

SREBP is bound to SCAP in membrane ER and held by Insig
> cholesterol levels fall, release Insig, move Scap+SREBP to Golgi membrane
> Activation, serine proteases cleave and release SREBP to move to nucleus and bind SRE (sterol regulatory element)

175
Q

Protease activities in activation SREBP

A

Serine protease cleaves bond between regulatory domain and transcription factor domain with DNA binding domain. A metalloprotease with Zn2+ cleaves the TF from the transmembrane domain to release it to move to SRE.

176
Q

Binding of SREBP to SRE promotes the expression of these two proteins (and more)

A

-HMG-CoA reductase
-LDLR

177
Q

How is SREBP held into ER when there is cholesterol?

A

SCAP has a sterol binding domain which keeps it (with SREBP throgh regulatory domain) bound to Insig in ER membrane. When there are low sterol levels, SCAP changes conformation and releases Insig and can travel to Golgi.

178
Q

Function cholesterol in membrane flexibility

A

-Makes the membranes stiff > against the cold: antifreeze

179
Q

Cholesterol as base for bile acids and steroid hormones: what happens

A

CYP (cytochrome P450 monooxygenases) enzymes add OH group by using O2 to the carbon chain (no ring) of cholesterol.

180
Q

Where does the bile acid formation occur? To which bile acids is cholesterol converted?

A

In the liver:
Cholesterol to Glycocholate or Taurocholate (different side chains)

181
Q

Functions bile acid

A

Solubilization of lipids in food through micel formaion and uptake by intestine
> and secreting cholesterol from the body

182
Q

How do gallstones appear

A

It are cholesterol crystals due to excess cholesterol secretion via bile (in gall bladder)

183
Q

Steroid hormone formation through cholesterol

A

Cholesterol (C27)&raquo_space; progestagens (C21)
Progestagens fates
-Glucocorticoids like cortisol (C21)
-Mineralocorticoids like aldosteron (C21) (get minerals in place)
-Androgen (C19) (> Estrogens (C18)). (sex hormones: development)
> all essential
> ligands for nuclear receptors

184
Q

Cortisol function

A

Fight or flight
> suppresses immune system
> enhanced gluconeogenesis and enhanced insulin
> Circadian rythm (sleep/awake)

185
Q

Cortisol pathology

A

-Too much: syndrome of Cushing (too much fat)
-Too little: Addisons disease

186
Q

How is vitamin D made?

A

From dehydrated cholesterol which is isomerized (one ring opened) through UV-light from the sun. and some reactions afterwards

187
Q

Function VitD

A

Calcium and phosphorus maintenance

188
Q

Too little vitD:

A

-Problems with bones and muscle (Rickets)
-Depressions
-Cancer
-Immune system

189
Q

Too much vitD

A

Toxic

190
Q

HC18: Problem cholesterol degradation

A

We cannot degrade it! excretion to get rid of it.

191
Q

How do we get rid of cholesterol?

A

Bile acid synthesis in liver to excrete with GI tract through bile bladder

192
Q

Cholesterol accumulation in the blood leads to…

A

atherosclerosis

193
Q

What happens too adipocytes when much of TAGs are stored?

A

They become larger and if too much energy is taken up they will proliferate

194
Q

In which cells are TAGs made?

A

Adipocytes and liver cells
> fuel, energy storage

195
Q

Lipids are insoluble to water. How are they transported in blood?

A

With lipoproteins

196
Q

What are lipoproteins?

A

Vesicles floating around in the blood which form a cell around a lipid content. (like a micelle)

197
Q

Outside lipoprotein particle? And inside?

A

Phospholipids, unesterified cholesterol, apolipoproteins.
Inside: Cholesteryl esters and TAGs

198
Q

Lipoproteins are made and secreted by which cells?

A

Intestine and liver cells

199
Q

Why are apolipoproteins important?

A

These proteins are involved in docking of the lipoprotein to the right receptor of a cell which is in need of lipids.

200
Q

Lipoproteins in plasma give a … look

A

milky

201
Q

Classes of lipoproteins and characteristics

A

-Chylomicrons > secreted by intestine cells with dietary, taken up, lipids. These travel trough the blood via the lymph and they shrink before passing the liver because bypassing tissues suck up lipids.
-VLDL (very low density): secreted by liver.
-LDL: product of VLDL with TAGs sucked up by tissues (higher concentration cholesterol)
-HDL (high dense) > secreted by liver cells to take up cholesterol from peripheral cells and bring it to the liver

202
Q

Density (ratio protein / lipid) in lipoproteins

A

-Chylomicrons: high percentage TAG, less protein
-HDL: high percentage protein and less lipids
-VLDL: lowest percentage protein
so on

203
Q

In a serum gradient, lipids float. Different density lipoproteins can be distinguished in three layers. How?

A

Lower layer: HDL
Middle layer: LDL
Top layer: VLDL

204
Q

How are chylomicrons called after TAGs are taken up (and before uptake by the liver)?

A

Chylomicron remnants

205
Q

Cholesterol cannot be degraded, thus needs to be secreted. Name the pathways of cholesterol.

A

-Food > chylomicron remnants to liver
-Forward transport route of lipoproteins: VLDL > IDL > LDL (gradual uptake of TAGs) : LDL uptake by periphery.
-IDL and LDL can also be taken up by the liver (reverse sideroutes)
-Reverse transport route: HDL takes up cholesterol from periphery and transport to liver.
-Excretion by making bile acids and through feces.

206
Q

Which kind of layer of phospholipids is found on the lipoprotein surface

A

Monolayer

207
Q

Membrane component lipoprotein

A

The outside of the lipoprotein.

208
Q

Lipoprotein core

A

Triglycerides and cholesteryl esters

209
Q

Different lipoproteins are determined by the different….

A

apolipoproteins (determine recognition by receptors)

210
Q

How is cholesterol esterified?

A

The small polar group (hydroxyl group at end rings) is esterified with a FA which make the molecule solely hydrophobic instead of amphipathic, directing it to the lipoprotein core

211
Q

LDL carriers the Apolipoprotein? and HDL?

A

ApoB100
HDL”: ApoA1

212
Q

Lipid uptake

A

-Fat uptake by intestine (bile)
-Formation chylomicrons in intestine
-Via lymphatics to blood

213
Q

Half-life chylomicrons

A

2 hours

214
Q

How is VLDL converted to IDL and LDL

A

Tissues express LPL which breaks down TAGs to FAs and glycerol for uptake.
> LPL expressed via endothelial cells in capillaries.
> not produced by these endothelial cells
> also in chylomicrons to form chylomicron remanants

215
Q

How is LDL taken up by peripheral cells?

A

The whole LDL particle is taken up through receptor mediated endocytosis

216
Q

What happens to endosome with LDL and LDLR?

A

LDL transported to acid lysosome, fusion and degradation LDL, cholesterol and content into cytosol through transporters and recycling of the LDLR

217
Q

What happens to the balance of SREBP/LXR when there is much cholesterol in the cell

A

Balance towards LXR.

218
Q

Which enzyme converts cholesterol (free) to a cholesterol ester in the peripheral cell?

A

ACAT: Acyl-CoA cholesterol acyl transferase

219
Q

Functions cholesterol esters in peripheral cells

A

-Storage
-Protect membrane

220
Q

Which transcription factor rules in the peripheral cell when the reverse route is activated?

A

LXR

221
Q

How is HDL produced in the liver (content)?

A

As an empty vesicle: only membrane and a bit of protein
> forms a bilayer disc because of no content.

222
Q

Which transporter is essential for the transport of cholesterol from the PM to the HDL membrane?

A

ABCA1: ATP-binding cassette transporter-1

223
Q

What does a defect in ABCA1 cause?

A

Tangiers disease, high risk for cardiovascular problems since you cannot get rid of cholesterol

224
Q

What are other causes of Tangiers disease?

A

-Apo-A1 defect (apolipoprotein of HDL defect)
-LCAT defect

225
Q

Function LCAT

A

Lecithine cholesterol acyl transferase (remember cholesterol-ester is esterified with a acyl)
- Cholesterol + Lecithine (PC: phosphatidylcholine) > Cholesterol-ester + Lysolecithine.
-(middle acyl group of lecithine transferred to cholesterol hydroxyl group.)

226
Q

Result LCAT conversion

A

Increased LysoPC in the HDL membrane (product of reaction to form cholesterol ester).
> cholesterol becomes insoluble: to HDL core

227
Q

Where is LCAT located?

A

On the HDL (bilayer disc)

228
Q

Extra function ApoA1

A

Promotes LCAT

229
Q

Reverse to transfer of CE (cholesterol ester) to forward pathway

A

CETP (cholesteryl ester transfer protein)
> Transfers CE from HDL to VLDL/IDL/LDL
> CETP can also transfer some TAGs and PLs (phospholipids) from LDL to HDL.
> IDL and LDL will mostly be taken up by the liver (expresses LDLR as well) and thus CE will arrive in liver for excretion also via this route, so HDL can take up more CE from the periphery before it passes the liver.

230
Q

Liver decides the cholesterol fates, which ones?

A

To VLDL
To bile / faeces

231
Q

Is reabsorption of cholesterol from intestine after excretion by bile good?

A

Yes

232
Q

Homozygous Familial Hypercholesterolemia (FH)

A

No functional LDLR: no life possible

233
Q

Heterozygous Familial Hypercholesterolemia

A

Half the number of LDLR is functional.

234
Q

Problems with FH

A

LDL accumulaion in the arteries: inflammation and atherosclerosis risk.

235
Q

Treatments FH

A

-Statins
-Cholestyramine/ ezetimibe

236
Q

Statins function

A

Inibit HMG-CoA reductase as competitive inhibitor and thereby reduce cholesterol biosynthesis

237
Q

Cholestyramine and Ezetimibe function

A

Bile abosorption inhibitors > then, more bile acids should be made, so cholesterol is used to make new bile acids, because bile absorption is inefficient.

238
Q

Bile secretion and uptake

A

-secretion: bile salts are formed from cholesterol and transport cholesterol from liver to feces
-Uptake: bile solubilizes lipids from food and is absorbed by intestine.

239
Q

LDL accumulation cause

A

Force into a corner which leads to inflammation
> accumulation is the outer curvatures of an S form of artery.
> low shear stress areas: uptake lipids from blood due to local flow profile.

240
Q

Atherosclerosis may lead to heart …

A

infarction, because the coronary arteries has many curves or side chains where atherosclerosis can occur

241
Q

How is inflammation induced in atherosclerosis?

A

Macrphages accumulate to clear the lipids
> take up the lipids

242
Q

Foam cell formation

A

Macrophage stress: macrophages get full of lipids: secrete stress cytokines > inflammation > macrophage stress (they get immobile because there is no cholesterol degradation)

243
Q

Pathway macrophage stress

A

Uptake LDL via scavenger receptors and NOT VIA LDLR
> no degradation cholesterol: become immobile > stress > secretion inflammation cytokines > more inflammation
> efflux via ABCA1 cannot cope with lipids,

244
Q

Macrophage accumulation and effects

A

To prevent the macrophages from bursting, the endothelial muscle cells will grow over the macrophages.
> eventually the macrophages die
> Formation cholesterol crystals (irreversible)
(from fatty streak: macrophage accumulation (reversible) to lesion (irreversible))

245
Q

What is a risk factor for infarct when atherosclerosis?

A

Exercise > more blood flow > plaques can burst > blood clotting > big clot closes the artery > infarct

246
Q

What is SRB1 (scavenger receptor class B type 1)?

A

Receptor which binds HDL by peripheral cells

Medical Biochemistry and Pathophysiology (16 decks)

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