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3) Metabolism and Human Nutrition > 2. Introduction to Lipids and Lipoprotein Metabolism (Part III) > Flashcards

2. Introduction to Lipids and Lipoprotein Metabolism (Part III) Flashcards

1
Q

How can we know where a protein is found within a cell?

A

Attach a green fluorescent protein (GFP) to create a hybrid

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2
Q

Where is the SWEET transporter found?

A

In the plasma membrane, according to the GFP

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3
Q

How did scientists construct a synthetic transgene to direct the overexpression of human LDLR in the liver of mice? What was particular about this sequence?

A
  • Portion of the LDLR as genomic sequence from the 5’ end
  • Middle: RNA
  • Portion of the LDLR as genomic sequence from the 3’ end
  • The sequence is MUCH smaller (1/10)
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4
Q

What do LDLR transgenic mice (overexpression of LDLR) fed a low cholesterol diet display?

A

Low blood LDL cholesterol

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5
Q

What do LDLR transgenic mice (overexpression of LDLR) exhibit in terms of hypercholesterolemia?

A

Resistance to diet-induced hypercholesterolemia

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6
Q

What does size-exclusion chromatography allow for? How?

A
  • Separation of particles based on their size
  • Large particles cannot enter the matrix and are excluded
  • Small particles enter the matrix
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7
Q

What kind of particles elute first in size-exclusion chromatography? Why elute later?

A
  • Large first

- Small later

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8
Q

Which lipoproteins would come out first in size-exclusion chromatography?

A
  • Chylomicrons
  • VLDL
  • IDL/LDL
  • HDL
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9
Q

How are the VLDL and LDL levels of mice? Why?

A
  • Low VLDL
  • NO LDL
  • Because they are very efficient at getting rid of lipoproteins in blood
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10
Q

What kind of lipoproteins does a non-transgenic mice consuming a low-fat diet contain?

A

ONLY HDL

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11
Q

What kind of lipoproteins does a non-transgenic mice consuming a high-fat diet contain?

A
  • Accumulation of VLDL, IDL/LDL, and HDL

- There is NO spike in LDL, as they are extremely efficient

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12
Q

Transgenic mice display a low level of HDL. Would they develop atherosclerosis?

A

No, since there is no circulating LDL

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13
Q

What kind of lipoproteins does a transgenic mice consuming a low-fat diet contain?

A
  • Much less LDL

- Because they express more LDLR, which increases the LDL pickup by the liver cells

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14
Q

What kind of lipoproteins does a transgenic mice consuming a high-fat diet contain?

A
  • Little change in the amount of VLDL, and HDL

- They are resistant to hypercholesterolemia

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15
Q

What does targeted gene disruption permit?

A
  • Very specific mutations (gene deficiencies) to be created

- Allows direct assessment of gene function

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16
Q

Differentiate global mutations and local mutations.

A
  • Global: whole animal

- Local: specific tissues, or even specific cells

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17
Q

Describe the mechanism for targeted gene disruption.

A
  1. Embryonic stem cells are collected from the blastocysts
  2. They are grown in a dish
  3. Targeting vector (DNA) is directed into a specific site
  4. Cell is screened, isolated, and injected into a blastocyst
18
Q

What does a targeting vector induce?

A

Induces a disruption of the local gene

19
Q

What is the manipulated ES injected in?

A

Into the blastocysts

20
Q

Differentiate a heterozygote and a chimera.

A
  • Heterozygote: contains complete genomes of the same background
  • Chimera: contains two genetic backgrounds
21
Q

What does the production of a chimera from a wild-type genome mouse and a modified genome mouse tell us?

A
  • That the participation of the ES cell donor genome was limited, because the progeny mouse is mostly white
  • Only portions of the mouse were formed by the ES cell that was manipulated
22
Q

What do we do to the mice that display a modified genome?

A

They are bred so we can uncover their particularities as a colony

23
Q

What was the proof of concept of what we find in human FH?

A

Targeted disruption of the LDLR gene in mice

24
Q

What do we need to do to go past the association between LDLR and FH?

A
  • Start with normal
  • Take out the gene encoding for the LDLR in mice
  • Reproduce the disorder to have a proof of concept
25
Q

How are mice naturally resistant to diet-induced hypercholesterolemia?

A

Cyp7a1 gene

26
Q

What is a difference between human and mouse hypercholesterolemia?

A

Atherosclerosis is premature in humans, but mice are only more susceptible

27
Q

What happens when there is targeted gene disruption of the LDLR gene in mice when they are fed a low-fat diet? What about when they are fed a high-fat diet?

A
  • They exhibit an increase in LDL concentration in the blood

- The response is elevated when they are fed a high-cholesterol and high-fat diet

28
Q

What are LXRs activated by? When would they be stimulated?

A
  • Activated by oxysterols

- Stimulated when cellular oxysterol concentrations increase

29
Q

What genes involved in sterol and fat metabolism are controlled by LXR-alpha?

A
  • Cyp7a1 (stimulates)
  • SREBP-1c (stimulates)
  • ABCA1 (stimulates)
  • ABCG5/G8 (stimulates)
  • ACAT (inhibits)
  • NPC1L1 (inhibits)
30
Q

What is the effect of targeted disruption of the LXR-alpha gene in mice in terms of hepatic lipids?

A
  • Liver mass increases (fatty liver)
  • Cholesterol concentration increases substantially
  • NO effect on TG metabolism
31
Q

How does the abundance of Cyp7a1 change if they are fed a diet high in cholesterol?

A

Increases

32
Q

How does the abundance of Cyp7a1 change if the mice undergo targeted disruption of the LXR-alpha gene?

A
  • No difference

- Without LXR-alpha, there is no change

33
Q

Which SREBP is embryonic lethal? What does that tell you?

A
  • SREBP-2

- Means that it is very important in the functioning of cells

34
Q

Where is NPC1L1 expressed at high levels in humans and mice?

A
  • Liver and small intestine (humans)

- Mainly the small intestine (mice)

35
Q

What is the function of ezetimibe?

A
  • Competitive inhibitor of NPC1L1

- Competes with cholesterol for uptake by enterocytes

36
Q

What is the function of ABCG5/G8?

A

Getting rid of cholesterol from enterocytes

37
Q

What is the function of NPC1L1?

A

Bringing in cholesterol from enterocytes

38
Q

What does free cholesterol become within the enterocyte to induce LXR activity? What does that increase?

A
  • Oxysterol

- ABCG5/G8

39
Q

What transporter does free cholesterol induce directly to get rid of cholesterol?

A

ABCA1

40
Q

Do bile acids have an impact on cholesterol absorption in mice?

A

Probably not too much

41
Q

How much cholesterol do mice absorb due to NPC1L1?

A

80% (20% does not go through NPC1L1)

42
Q

Is the remaining 20% of cholesterol that is not absorbed by NPC1L1 affected by ezetimibe?

A

No

3) Metabolism and Human Nutrition (17 decks)

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