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MCD- metabolism > cholestrol > Flashcards

cholestrol Flashcards

1
Q

What is cholesterol

A

Cholesterol is a steroid.
It controls the rigidity of the phospholipid bilayer.
High temp: stabilises membrane and raises melting point
Low temp: intercalates between phospholipids to prevent them from clustering and stiffening

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2
Q

How many carbons in cholesterol?

A

27

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3
Q

Where is cholesterol made and from what?

A

Liver and from acetyl coA.

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4
Q

What controls HMG-CoA reductase

A

Is under negative feedback control by the end product cholesterol, the intermediate mevalonate and bile salts.

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5
Q

where does synthesis of cholesterol take place of the organelles?

A
  • synthesis of IPP occurs in cytoplasm
  • condensation of IPP to form squalene occurs in cytoplasm
  • cyclisation and demethylation of squalene happens in ER
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6
Q

What is pregnenolone?

A

Cholesterol is the basis of all 5 classes of steroid hormones (Progestins, Glucocorticoids, Mineralocorticoids, Androgens and Estrogens) via the precursor pregnenolone which is generated from cholesterol by the action of the enzyme desmolase.
Location of pregnenolone is adrenal gland

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7
Q

what type of vitamin is cholestrol also a part of, and a lack of what leads to what disease?

A

Cholesterol is a major source of vitamin D3.
Deficient of vitamin D3 leads to rickets.
Calcitriol plays a major role in calcium metabolism.

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8
Q

what is the product of cholestrol breakdown?

A

Bile salts

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9
Q

How is bile salts made from cholesterol

A

Cholesterol is converted into primary bile salt glycocholate and taurocholate

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10
Q

Describe the structure of lipoproteins

A
  • Consist of a phospholipid monolayer containing cholesterol and proteins: apoproteins (allows particle to be recognised by tissue)
  • packed within the core of the lipoprotein are a mixture of cholesterol esters and triacyclglycerols
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11
Q

Why and how are cholesterol esters made?

A

synthesised in the plasma from cholesterol and the acyl chain of phosphatidylcholine (lecithin) via a reaction catalysed by lecithin cholesterol acyltransferase.
Makes cholesterol esters more hydrophobic than cholesterol so can be packed more tightly within the lipoprotein core.

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12
Q

How else can cholesterol esters be made and where does this happen?

A

Enzyme: Acyl CoA-acyltransferase can generate cholesterol esters from long chain fatty acyl coA species.
ACAT is an intracellular enzyme and acts on cholesterol taken up by endocytosis.

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13
Q

What are the types of lipoproteins and what is it based on?

A

Come in 5 forms:

  • chylomicrons
  • Very low density lipoproteins
  • Intermediate density lipoproteins
  • Low density lipoproteins
  • High density lipoproteins

VLDL are the precursors of IDLs and IDLs are the precursors of LDL.

Based on their density.
-have different apoprotein which allows them to be recognised by different cell types.

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14
Q

Where is lipoprotein lipase located and what does it do?

A

On a variety of tissues e.g. adipose, heart and skeletal.

-catalyses the hydrolysis of the triacyclglycerols in chylomicrons to glycerol and fatty acid

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15
Q

state the difference between HDL and LDL?

A

HDL: take cholesterol from peripheral tissues back to the liver, so lower total serum cholesterol
LDL: transport cholesterol from liver to peripheral tissues, prolonged elevation leads to atherosclerosis

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16
Q

Give an example of a LDL problem?

A

Familial hypercholesterolaemia:

  • Monogenic dominant trait.
  • homozygotes have severe atherosclerosis and coronary infection in adolescence have 5 times higher cholesterol
  • heterozygotes have 2-3 times higher
17
Q

Describe the LDL receptor and how is this in severe FH

A

LDL are taken up by specific cell-surface receptor by receptor mediated endocytosis

  • Ligand binding domain
  • EGF precursor homology domain
  • O-linked carbohydrate domain
  • TM domain
  • Cytoplasmic domain

lacked functional LDLRs with those that have severe FH

18
Q

what is Receptor mediated endocytosis of LDLs

A

LDLRs send LDLs to early endosome.
At the early endosome, the LDLRs are recycled to the plasma membrane
LDLs are transferred to lysosomes where it is degraded to give free cholesterol.

19
Q

What Vitamin is synthesised from cholesterol?

A

Vitamin D3

20
Q

Describe the role of cholesterol in signalling.

A

Cholesterol and sphingolipids form lipid rafts that are involved in localising proteins involved in signalling

21
Q

How do statins reduce the accumulation of cholesterol? Give an example.

A

Statins are HMG-CoA Reductase inhibitors Lovastatin – competitively inhibits HMG-CoA Reductase

22
Q

What do Resins and Sequestrants do?

A

Hide bile acid-cholesterol complexes and prevents reabsorption by the intestines Lowers LDL levels Raises HDL levels

23
Q

5 classes of the LDLR mutation

A

CLASS I:
Mutation in LDLR promoter/frameshift/deletion - LDLR is not synthesiSed.

CLASS II:
Mutation throughout the coding region - LDLR is not properly transported from the ER to Golgi leading to low cell surface expression.

CLASS III:
Mutation in region encoding N-terminus - LDLR does not bind LDL effectively

CLASS IV:
Mutation in the cytoplasmic domain - LDLR: LDL complex does not cluster in clathrin-coated pits for receptor-mediated endocytosis.

CLASS V:
Mutation in EGFP domain - LDL is not released from the receptor in the endosome and LDLR is not recycled back to the cell surface.

24
Q

How are the 5 classes steroid come about> from what?

A

Cholesterol is the basis of all 5 classes of steroid hormones (Progestins, Glucocorticoids, Mineralocorticoids, Androgens and Estrogens) via the precursor pregnenolone which is generated from cholesterol by the action of the enzyme desmolase.
All 5 classes of steroid hormones come from pregnenolone:

Cholesterol (27C) –>
Pregnenolone (21C) –>
Progestagens (21C) –>
Glucocorticoids (21C) / Mineralocorticoids (21C) / Androgens (19C) –> Estrogens (18C)

25
Q

Covalently attachment of isoprenoids such as farnesyl or geranylgeranyl to proteins gives them what chief property?

A

ability to be anchored in membranes

26
Q

How is Vitamin D synthesised from cholesterol?

A

7-dehydrocholesterol —> Pre-vitamin D3 (under UV light)
Pre-vitamin D3 —> Vitamin D3 (cholecalciferol)
Vitamin D3 - Calcitriol (1,25-dihydroxycholecalciferol) (by hydroxylation)

27
Q

How do LDL looks and HDL?

A

With a size of over 20nm and with more than 40% of the lipoprotein’s weight made up of cholesterol esters, the liporotein is a low density lipoprotein (LDL). LDLs transport cholesterol synthesized in the liver to peripheral tissues.

-HDL has a size of 8-10 nm

28
Q

Describe the process of cholestrol biosynthesis?

A

1 . Condensation of 2 Acetyl-CoA molecules to form Acetoacetyl CoA.

  1. Condensation of another Acetyl-CoA molecule to form HMG-CoA.
  2. HMG-Co-A is reduced to generate mevalonate.
  3. Mevalonate undergoes sequential phosphorylation at the hydroxyl groups at position 3 and 5, followed by decarboxylation to form 3-Isopentenyl pyrophosphate.
  4. Isopentenyl pyrophosphate is isomerised to dimethylallyl pyrophosphate by Isopentenyl pyrophosphate ismorase.
  5. This then condenses twice with isopentenyl pyrophosphate to form 15C Farnesyl pyrophosphate.
  6. 2 molecules of Farnesyl pyrophosphate condense to form 30 carbon squalene and 2 molecules of pyrophosphate. This uses the reducing power of NADPH.
29
Q

How is cholestrol made from squalene?

A
  1. Squalene is REDUCED in the presence of oxygen and NADH to form squalene epoxide.
  2. Squalene epoxide lanosterol cyclase catalyses formation of Lanosterol.
  3. 19 steps and decarboxylation of 2 CO2 to produce cholestrol
30
Q

What is special about the arrangement of squalene epoxide?

A

Has a different c=c bond distribution priming the molecule for carbon ring fusion.

31
Q

what are targets for statins?

A

HMG –CoA reductase

32
Q

Describe the cycle of chylomicrons?

A

Chylomicrons (CMs) are transported via the lymphatics into the bloodstream and broken down by the enzyme Lipoprotein lipase located on the capillary endothelial cells lining a variety of tissues including adipose, heart and skeletal muscle. The triacylglycerols within the chylomicrons are hydrolysed to glycerol and fatty acids, the latter undergoing β-oxidation. Glycerol is returned to the liver for use in gluconeogenesis

33
Q

what is the overall biosynthesis of cholestrol?

A
  1. Synthesis of mevalonate, a reduced C6 species from 3 Acetyl-CoA units.
  2. Activation of mevalonate to isopentenyl-PP (isoprene unit), a C5 precursor which is elongated to a squalene, a C30 intermediate species. Condensation of 6 IPP to form squalene
  3. Cyclisation and demethylation of squalene by monooxygenases to give cholsterol.(ER).

MCD- metabolism (11 decks)

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