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Flashcards in Metabolism 8 Deck (25)
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1
Q

Cholesterol can change interactions with the cytoskeleeton

A

T

2
Q

What are the 3 parts of biosynthesis of cholesterol?

A
  1. Synthesis of isopentyl pyrophosphate.
  2. Condensation of 6 molecules of isopentyl pyrophosphate, forming squalene.
  3. Squalene cyclisation and demethylation by monooxygenases, giving cholesterol.
3
Q

Explain the biosynthesis of cholesterol (upto squalene).

A
  1. 2 acetyl-CoA molecules condensed, forming acetoacetyl CoA
  2. Another acetyl-CoA molecule condensed with acetoacetyl CoA. Forms HMG-CoA.
  3. HMG-CoA reduced, generating mevalonate.
  4. Hydroxyl groups at position 3 and 5 are then sequentially phosphorylated and decarboxylated. Forms 3-isopentenyl pyrophosphate.
  5. Isopentenyl pyrophosphate is isomerised to dimethylallyl pyrophosphate by isopentenyl pyrophosphate isomerase.
  6. Dimethylallyl pyrophosphate is then condensed with a unit of isopentenyl pyrophosphate, forming geranyl pyrophosphate.
  7. 3rd isopentenyl pyrophosphate molecule condenses with geranyl pyrophosphate, forming 15C Farnesyl pyrophosphate.
  8. 2 farnesyl pyrophosphate molecules condense to form 30C squalene and 2 molecules of pyrophosphate.
4
Q

How is squalene cyclised to cholesterol?

A

3 steps.

  1. Squalene reduced in presence of oxygen and NADPH to form squalene epoxide.
  2. Squalene epoxide lanosterol-cyclase catalyses lanosterol formation. 4 rings formed.
  3. Lanosterol reduced and 3 methyl units removed, generating cholesterol.
5
Q

What do all 5 classes of steroid hormones come from?

A

Pregnenolone (desmolase catalyses cholesterol conversion)

6
Q

Vitamin D is synthesised from cholesterol. How?

A

Through UV light

7
Q

Talk to me about bile salts

A
  1. Have hydrophobic and hydrophilic face.
  2. Form micelles, where hydrophilic faces face away from triacylglycerols (TAGS) and hydrophobic faces point towards TAGS.
  3. Emulsification of fats in intestine.
8
Q

Describe lipoproteins

A

Lipids are insoluble in aqueous solutions, posing transportation problems.

Lipids are packaged within lipoproteins (consist of phospholipid monolayer containing cholesterol and apoproteins).

In the core of a lipoprotein there is a cholesterol ester and TAGs.

9
Q

What does apoprotein do?

A

Allow particle to be recognised by the tissue

10
Q

How is cholesterol ester synthesised (for the lipoprotein core)?

A
  1. In the plasma, from cholesterol and the acyl chain of phosphatidylcholine.

Catalyst: lecithin cholesterol acyltransferase (LCAT)

  1. Alternatively, Acyl CoA acyltransferase (ACAT) could be used. It can generate cholesterol esters from long chain fatty acyl CoA species.

ACAT is an intracellular enzyme acting on cholesterol taken in by endocytosis.

11
Q

Why is cholesterol made into cholesterol esters?

A

Makes cholesterol esters more hydrophobic than cholesterol, and can pack more tightly in lipoprotein core.

12
Q

What are the classifications of Lipoproteins?

A

BASED ON DENSITY

  1. Chylomicrons (CM)
  2. Very Low Density Lipoproteins (VLDL)
  3. Intermediate Density (IDL)
  4. Low density Lipoproteins (LDL)
  5. High density Lipoproteins (HDL)

Each lipoprotein has varying apoprotein content so is recognised by different cell types

13
Q

What happens to fats when they are absorbed and packaged into chylomicrons?

A

The chylomicrons travel in the lymphatic duct from the intestines to the thoracic duct and subclavian vein

14
Q

What are the points of entry of chylomicrons entering the bloodstream?

A

Thoracic duct and subclavian vein

15
Q

Where is lipoprotein lipase located?

A

Capillary endothelial cells, lining a variety of tissues

16
Q

What do lipoprotein lipases do?

A

Catalyse hydrolysis of TAGs (in chylomicrons) to glycerol and fatty acids.

17
Q

How is lipoprotein activated?

A

Apoprotein C-2 helps

18
Q

What happens to the glycerol produced from lipoprotein lipase?

A

Goes to liver for use in gluconeogenesis

19
Q

Familial hypercholesterolaemia. Describe.

A
  1. Inherited as a monogenic dominant trait
  2. Homozygotes severely affected, have a serum level 5x higher than normals
  3. Homozygotes can have severe atherosclerosis / coronary infection in adolescence.
20
Q

What do HDLs do?

A

Take cholesterol from peripheral tissues back to liver for use/disposal. Lower total serum cholesterol

21
Q

What do LDLs do?

A

Transport cholesterol from liver to peripheral tissues.

22
Q

Describe receptor mediated endocytosis of LDLs

A
  1. LDLRs receive LDLs and send them into early end-some.
  2. Here the LDLRs are recycled back to the plasma membrane.
  3. LDLs transferred to lysosomes where they are degraded to give free cholesterol.
23
Q

Mutations in which gene result in familial hypercholesterolaemia?

A

LDLR gene

24
Q

What are the 5 classes of mutations of the LDLR gene?

A
  1. Class 1. Mutation in LDLR promoter/frameshift/deletion. LDLR not synthesised.
  2. Class 2. Mutation throughout coding region. LDLR not transported properly from ER to golgi, so low cell surface expression.
  3. Class 3. Mutation in region encoding n terminus. LDLR doesn’t bind effectively to LDL.
  4. Class 4. Mutation in cytoplasmic domain. LDLR-LDL complex doesn’t cluster in Clathrin coated pits for receptor mediated endocytosis.
  5. Class 5. Mutation in EGFP domain. LDL not released from receptor in endosome and LDLR not recycled back to cell surface.
25
Q

How can hypercholesterolaemia be controlled?

A
  1. HMG-CoA reductase inhibitors.
    - AKA statins
    - Lovastatin is a competitive inhibitor of HMG-CoA reductase
  2. Resins/Sequestrants
    - Bind / sequester bile acid-cholesterol complexes, so they cannot be reabsorbed by the intestine. Lowers LDL levels, raises HDL levels.