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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
Q

_____% dietary cholesterol is absorbed

A

50% dietary cholesterol is absorbed

26
Q

Factors influencing cholesterol absorption in the intestine

A
  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
Q

ABCG5 & ABCG8 influence _________. How?

A

=> Absorption in the intestines

=> Binding Casette transporter proteins pump cholesterol BACK into intestinal lumen.

28
Q

How do cholesterol lowering margarines work?

A

Packed full of plant sterols that compete with dietary cholesterol for absorption

29
Q

The 1st Lipoprotein in Reverse Cholesterol Transport is _____

A

Nascent HDL

30
Q

What is nascent HDL

A

Immature HDL particle
Has Apoprotein and phospholipid coat
BUT is LIPID POOR (doesn’t contain any esterified cholesterol)

31
Q

What is/are the source(S) of HDL?

A

(1) Secreted by liver & intestine

(2) Byproduct of CM & VLDL metabolism

32
Q

How is nascent HDL produced from CM & VLDL metabolism?

A

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
Q

How is cholesterol collected from peripheral cells?

A

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
Q

What transporter triggers movement of FC OUT of peripheral cells?

A

ABCA1

Stimulated by binding to APO-CII on HDL

Causes FC to move OUT of cell and be absorbed by HDL particle

35
Q

What receptors on the liver are activated to cause HDL particle to be removed from circulation?

A

SCAVENGER RECEPTORS (SRB1=scavenger receptor B1; expressed on macrophages/liver/endocrine organs/arteries)

36
Q

At what stage does HDL particle become ‘mature’?

A

When it converts FC ==> CE via LCAT

37
Q

What is TANGIER DISEASE?

A

Mutation in ABCA1…

Truncated region means can’t be transported across cell .: accumulation of cholesterol inside cells

38
Q

Mutation in _____ leads to tangier disease?

A

ABCA1

39
Q

ABCA1

A

Binding cassette transporter protein
Highly expressed in macrophages
Critical in forming HDl
Triggers movement of FC across membrane to nascent HDl

40
Q

Apo-A1

A

Activates LCAT

41
Q

LCAT

A

Converts nascent HDL –> mature HDL

FC–> CE (in HDL)

42
Q

SR-B1

A 
Scavenger receptor B1 
Expressed on 
-macrophages 
-liver/endocrine organs
-arteries (leads to internalisation of LDL/cholesterol = formation of foam cells = atherosclerosis=CHD)
43
Q

CETP

A

Cholesterol Ester Transfer Protein

Involved in exchanging lipids between HDL & other lipoproteins

44
Q

Activation of SR-B1 in arteries can lead to…

A

Formation of FOAM CELLS (as cholesterol esters move into ells) = ATHEROSCLEROSIS

45
Q

Reverse cholesterol Transport

A 
HDL 
Released to circulation
Picks up cholesterol from peripheral cells
Returns them to liver 
Recycled
46
Q

Why is HDL good?

A

Reduces accumulation of cholesterol in peripheral cells (.: reduces risk of CVD)

47
Q

What happens to cholesterol once it is returned to the liver by ____?

A

HDL

1) Catabolised to bile acids (BA
(2) BAs & FC secreted into Bile
(3) Excreted in Faeces

48
Q

Why is HDL protective against atherosclerosis?

A

(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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