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Physiology 3003 > Lecture 15--HDL & Cholesterol > Flashcards

Lecture 15--HDL & Cholesterol Flashcards

1
Q

Function of cholesterol

A

> Structural

>Precursor (vitamin D, steroid hormones, bile salts)

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2
Q

Briefly outline vit D synthesis

A

7-dehydrocholesterol –UV light (irradiated)–> conversion in liver & kidney–>CALCITRIOL (active form)

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3
Q

Briefly outline steroid synthesis

A
  • *Cholesterol
  • -(conversion)–>
  • *PREGNENOLONE
  • -(conversion in renal cortex)–>
  • *Steroid hormones
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4
Q

What is the common intermediate in steroid synthesis from cholesterol?

A

PREGNENOLONE

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5
Q

Briefly outline bile salt synthesis from cholesterol?

A 
Cholesterol 
--(conversion)--> 
PRIMARY BILE ACIDS
--(conversion, intestines)-->
SECONDARY BILE ACIDS
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6
Q

What is the conversion of the PRIMARY & SECONDARY bile acids?

A

Primary –> Secondary

Cholic Acid ==> deoxycholic acid
Chenodeoxycholid Acid ==> Lithocholic Acid

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7
Q

What are the primary bile acids

A

1) cholic Acid

2) CHENODEOXYcholic Acid

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8
Q

What are the secondary bile acids?

A

1) DEOXYcholic acid

2) LITHOcholic acid

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9
Q

What causes Smith-Lemli-Optiz syndrome?

A

1) Due to a MUTATION IN DHCR7 gene =>
2) Can’t synthesise 7-DEHYDROCHOLESTEROL REDUCTASE
3) Means UNABLE TO SYNTHESISE CHOLESTEROL

Caused by mutation in gene DHCR7 which encodes 7-dehydrocholesterol reductase. In the absence of this enzyme cholesterol cannot be synthesised.

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10
Q

7-dehydrocholesterol reductase

A

essential enzyme in the synthesis of cholesterol

Mutation in DHCR7 gene leads to inability to synthesise cholesterol (Smith-Lemli-Optiz syndrome)

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11
Q

Symptoms of Smith-Lemli-Opitz Syndrome

+ Treatment

A

1) Cleft Palate
2) Microcephaly (small head)
3) Abnormal brain development
4) Dysmyelination
5) Congenital heart defects
6) Limb malformation

Treatment with dietary cholesterol supplementation

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12
Q

Cholesterol biosynthesis by what pathway?

A

The MEVALONATE PATHWAY

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13
Q

What is the MEVALONATE PATHWAY?

A

Cholesterol biosynthesis

Acetyl CoA –(HMG CoA Synthase)–> HMG CoA –(HMG CoA Reductase)–> Mevalonate –>–>Cholesterol

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14
Q

Cholesterol regulation by cells –HIGH CHOLESTEROL

A

ApoB100 binds to receptor
Internalised
Free cholesterol moves to Golgi

EFFECTS:
(1) Diminish HMG CoA REDUCTASE (=reduced mevalonate pathway/chol BIOSYNTHESIS from acetyl CoA)

(2) Diminish expression of LDL RECEPTOR (=diminish UPTAKE by cells)
(3) Increase Expression of ACAT (converts free chol–>esterified Chol = increases STORAGE)

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15
Q

Cholesterol regulation by cells –LOW CHOLESTEROL

A

=> transcription factors translocate to the nucleus when there is an absence of cholesterol.

(1) INSIG dissociates from ER
(2) SREBP cleaves from INSIG
(3) SREBP complexes with SCAP
(4) SREBP-SCAP move to golgi
(5) From golgi SREBP/SCAP move to nucleus (regulate cool synthesis)

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16
Q

INSIG

A

Nuclear transcription factor

Tethered to ER membrane when cool is present, dissociates when low cholesterol

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17
Q

SREBP

A

‘Sterol regulatory element binding protein’

LOW CHOL: Dissociates from INSIG, associates with SCAP & moves to golgi then to nucleus where it regulates cholesterol synthesis

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18
Q

Statin drugs ____________ b/c they have a _______ effect. What does this mean?

A

Statin drugs REDUCE THE RISK OF CVD b/c they have a PLEIOTROPIC effect.

They don’t just block HMG CoA reductase (=reducing cholesterol synthesis) they also:
1Diminish ACTIVATION of PLATELETS
2Diminish the THROMBOTIC EFFECT
3Diminish PROLIFERATION of smooth muscle cells
4Increase PLAQUE STABILITY

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19
Q

Cholesterol homeostasis

\_\_\_\_g/day (diet)
\_\_\_\_g/day (synthesised)
\_\_\_\_g/day (secreted to bile salts) 
\_\_\_\_g/day (secreted to bile) 
\_\_\_\_g/day (secreted to VLDL)

NET GAIN _____ g/day
NET LOSS ____g/day
NET (TOTAL)____g/day

A

+ 0.5 g/day (diet)

+ 1 g/day (synthesised)

  • 0.5 g/day (secreted to bile salts)
  • 1.0 g/day (secreted to bile)
  • 1.0 g/day (secreted to VLDL)

NET GAIN 1.5 g/day
NET LOSS -2.5 g/day
NET (TOTAL) -1.0 g/day

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20
Q

How is cholesterol ELIMINATED?

A

Primarily by conversion to bile acids and excretion in the faeces

21
Q

What are the mechanisms for cholesterol recycling?

A

(1) VASCULOSYSTEMIC CIRCULATION
(2) ENTEROHEPATIC CIRCULATION
(3) REVERSE CHOLESTEROL TRANSPORT

22
Q

What is VASCULOSYSTEMIC CIRCULATION?

A

VLDL released from liver to circulation & transitions to LDL/IDL which is re-uptaken by the liver

23
Q

What is ENTEROHEPATIC CIRCULATION?

A

Free cholesterol + Cholesterol in bile salts released (in bile) in intestine

24
Q

What is REVERSE CHOLESTEROL TRANSPORT

A

HDL picks up cholesterol from peripheral cells and returns it to the liver

25
_____% dietary cholesterol is absorbed
50% dietary cholesterol is absorbed
26
Factors influencing cholesterol absorption in the intestine
1. Competition with plant sterols 2. ABCG5 & ABCG8 (binding cassette transporter proteins pump cholesterol BACK into intestinal lumen.) 3. Cholesterol lowering drugs (EZETIMIBIBE acts on NIEMAN PICK LIKE protein (chol transporter protein)
27
ABCG5 & ABCG8 influence _________. How?
=> Absorption in the intestines | => Binding Casette transporter proteins pump cholesterol BACK into intestinal lumen.
28
How do cholesterol lowering margarines work?
Packed full of plant sterols that compete with dietary cholesterol for absorption
29
The 1st Lipoprotein in Reverse Cholesterol Transport is _____
Nascent HDL
30
What is nascent HDL
Immature HDL particle Has Apoprotein and phospholipid coat BUT is LIPID POOR (doesn't contain any esterified cholesterol)
31
What is/are the source(S) of HDL?
(1) Secreted by liver & intestine | (2) Byproduct of CM & VLDL metabolism
32
How is nascent HDL produced from CM & VLDL metabolism?
CM/VLDL ApoCII + lipoprotein lipase (capillaries) => TG hydrolysis => loss of TGs=> excess outer surface => Can be converted to SURFACE REMNANT => forms the basis for formation of the NASCENT HDL
33
How is cholesterol collected from peripheral cells?
REVERSE CHOLESEROL TRANSPORT HDL=> peripheral cells => ABCA1=> peripheral ells allow movement of free cool OUT => FC absorbed by HDL => FC converted to EC by LCAT => Mature HDL particle => binds to Scavenger receptors on Liver => removed from circulation => CE converted to FC => released into bile
34
What transporter triggers movement of FC OUT of peripheral cells?
ABCA1 Stimulated by binding to APO-CII on HDL Causes FC to move OUT of cell and be absorbed by HDL particle
35
What receptors on the liver are activated to cause HDL particle to be removed from circulation?
SCAVENGER RECEPTORS (SRB1=scavenger receptor B1; expressed on macrophages/liver/endocrine organs/arteries)
36
At what stage does HDL particle become 'mature'?
When it converts FC ==> CE via LCAT
37
What is TANGIER DISEASE?
Mutation in ABCA1... | Truncated region means can't be transported across cell .: accumulation of cholesterol inside cells
38
Mutation in _____ leads to tangier disease?
ABCA1
39
ABCA1
Binding cassette transporter protein Highly expressed in macrophages Critical in forming HDl Triggers movement of FC across membrane to nascent HDl
40
Apo-A1
Activates LCAT
41
LCAT
Converts nascent HDL --> mature HDL | FC--> CE (in HDL)
42
SR-B1
``` Scavenger receptor B1 Expressed on -macrophages -liver/endocrine organs -arteries (leads to internalisation of LDL/cholesterol = formation of foam cells = atherosclerosis=CHD) ```
43
CETP
Cholesterol Ester Transfer Protein | Involved in exchanging lipids between HDL & other lipoproteins
44
Activation of SR-B1 in arteries can lead to...
Formation of FOAM CELLS (as cholesterol esters move into ells) = ATHEROSCLEROSIS
45
Reverse cholesterol Transport
``` HDL Released to circulation Picks up cholesterol from peripheral cells Returns them to liver Recycled ```
46
Why is HDL good?
Reduces accumulation of cholesterol in peripheral cells (.: reduces risk of CVD)
47
What happens to cholesterol once it is returned to the liver by ____?
HDL | 1) Catabolised to bile acids (BA (2) BAs & FC secreted into Bile (3) Excreted in Faeces
48
Why is HDL protective against atherosclerosis?
(1) HDL Inhibits recruitment monocytes to arterial wall by INHIBITING EXPRESSION OF ADHESION MOLECULES (bind to surface of monocytes cause them to stick to arterial walls => foam cells) (esp with Apo-A1) (2) INHIBITS MITOSIS OF AORTIC SMOOTH MUSCLE CELLS (due to APO-E content of HDL), amount of mitosis of smooth muscle is strongly reduced with high HDL. (4) RELAXES PRE-CONTRACTED AORTA VIA ENZYME NITRIC OXIDE (NO) --NO mediates HDL in vaso-dilation of smooth muscle (in presence of NO-inhibitor HDL fails to produce a vasodilatory effect)

Physiology 3003 (15 decks)

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