Cholesterol Flashcards
(88 cards)
1
Q
Why is cholesterol important?
A
It is a critical component of cell membranes, signalling pathways, and a precursor for many important biomolecules
2
Q
What are the three primary sources of fats?
A
- The diet
- De novo biosynthesis (liver- making it from scratch)
- Storage depots in adipose
3
Q
How do sugars generate acetyl CoA?
A
sugars -> glucose -> pyruvate (outside mitochondria)-> pyruvate (inside mitochondria)-> acetyl CoA
4
Q
How do fats generate acetyl CoA?
A
Fats-> fatty acids (outside mitochondria)-> fatty acids (inside mitochondria)-> acetyl CoA
5
Q
What breaks down dietary fats?
A
Lipases
6
Q
What are needed to solubilize dietary fats?
A
Bile acids
7
Q
What does a lack of bile acids result in?
A
Steatorrhea (Fatty stool) - this is because majority of fat passes through the gut undigested and unabsorbed
8
Q
What produced bile salts?
A
Liver
9
Q
Where are bile salts stored?
A
gallbladder
10
Q
What do bile salts do in digestion?
A
They emulsify fats in the intestine and aid the digestion and absorption of fat soluble vitamins (A, D, E and K)
11
Q
What is Orlistat?
A
A potent inhibitor of gastric and pancreatic lipases
It is a chemically synthesised derivative of lipstatin
12
Q
What are the main side effects of Orlisats?
A
Steatorrhea, abdominal pain, urgency to defecate, increased flatus
13
Q
By how much does Orlistat reduce fat absorption?
A
30%
14
Q
Can orlistat treat obesity?
A
Yes, it has been shown that it is effective in treating obesity for up to 2 years
15
Q
what do lipoproteins do?
A
Transport lipids in the plasma
16
Q
Where are VLDL produced and what is their role?
A
Liver- endogenous fat transport
17
Q
Where are intermediate density lipoproteins sourced from and what is their role?
A
VLDL- LDL precursor
18
Q
Where are LDL sourced from and what is their role?
A
IDL- cholesterol transport
19
Q
Where are HDL produced and what is their role?
A
Liver- reverse cholesterol transport
20
Q
Where are chylomicrons produced and what is their role?
A
Intestine - dietary fat transport
21
Q
What do chylomicrons look like?
A
22
Q
Where are digested dietary products absorbed?
A
By the enterocytes that line the brush border of the small intestine
23
Q
What happens to triglycerides after they are resynthesised?
A
Triglycerides are resynthesised under the control of several enzymes prior to incorporation into chylomicrons (CM)
These are transported via lymphatics and on into the blood stream
24
Q
Where do chylomicrons acquire apoproteins from?
A
From HDL following release into the blood stream
25
How do chylomicrons enter into the blood stream?
Travel from the lacteals of the intestine into the thoracic duct and into the left subclavian vein from which they enter into the blood stream
26
Where is lipoprotein lipase located?
On the capillary endothelial cells lining a variety of tissues, including adipose, heart and skeletal muscle
27
What is the life cycle of chylomicrons?
smaller chylomicron thingy=> remnants of chylomicron
FFA=> free fatty acids
28
Why is glycerol retuned to the liver?
for use in gluconeogenesis
29
What is the primary role of cholesterol in the body?
Maintenance of cell membrane integrity - can increase or decrease the stiffness depending on the temperature and nature of the membrane
30
Where is most of the cholesterol in the body found?
In cell membranes, more than 90%
31
What is the dietary cholesterol uptake limited to in humans?
0.5g a day
32
How are all the physiological requirements for cholesterol met?
They are supplied by the liver through the de novo synthesis of cholesterol from Acetyl CoA
33
What are the 3 CORE steps of cholesterol biosynthesis?
1) Synthesis of isopentenyl pyrophosphate, an activated isoprene unit which serves as a key building block (in cytoplasm)
2) condensation of 6 molecules of isopentenyl pyrophosphate to form squalene (in cytoplasm)
3) cyclisation and demythylation of squalene by monoxygenase to give cholesterol (ER)
34
What is the first step in cholesterol biosynthesis? (1.1)
Acetyl CoA + Acetyl CoA = Acetoacetyl CoA (via B-ketothiolase)
Condensation of 2 Acetyl-CoA molecules to form Acetoacetyl CoA.
35
What is the second step of cholesterol biosynthesis? (1.2)
Acetoacetyl CoA + Acetyl CoA -> HMG-CoA
Condensation of another Acetyl-CoA molecule to form HMG-CoA - using HMG-CoA Synthetase (via HMG-CoA synthase)
36
What is the third step in cholesterol biosynthesis? (1.3)
HMG-Co-A is reduced to generate mevalonate.
37
What enzyme is used to convert HMG-CoA into Mevalonate?
HMG-CoA Reductase
38
Describe how HMG CoA is under negative feedback?
HMG-CoA reductase is under negative feedback control by the end product cholesterol, as well as intermediates bile salts and mevalonate
39
What is the fourth step in cholesterol biosynthesis? (1.4)
Mevalonate undergoes sequential phosphorylation at the hydroxyl groups at position 3 and 5, followed by decarboxylation to form 3-Isopentenyl pyrophosphate.
This activated isoprene unit is a useful building block for further synthesis.
40
What is the fifth step in cholesterol biosynthesis? (2.1)
Via an isomerisation reaction, isopentenyl pyrophosphate can form dimethylallyl pyrophosphate
This can condense with a unit of isopentenyl-PP to form the C10 compound geranyl-PP
A third isopentenyl-PP molecule is added to from the C15 intermediate farnesyl-PP
41
What is the sixth step in cholesterol biosynthesis? (2.2)
2 farnesyl-PP molecules condense to form C30 squalene plus 2 molecules of pyrophosphate
42
What is the seventh and final step of cholesterol biosynthesis? (3.1)
cyclisation and demythylation of squalene
43
Why is ubiquinone confined to the inner membrane of the mitochondria?
because it has lipophilic properties of the isoprene unit
44
What is cholesterol the precursor of?
Pregnenolone
45
How does cholesterol turn into pregenolone?
the enzyme desmolase
46
What comes from progenolone?
all 5 classes of steroid hormones
47
What are the 5 classes of steroid hormones?
Progestagens (C21)
Glucocorticoids (C21)
Mineralocorticoids (C21)
Androgens (C19)
Oestrogens (C18)
48
Describe the synthesis of Vitamin D from cholesterol?
7-Dehydrocholesterol in the skin under UV is converted into Pre Vitamin D3. This is then converted into Cholecalciferol (Vitamin D3).
The cholecalciferol then undergoes hydroxylation using 25-Hydroxylase to form 25-OH Cholecalciferol.
Then, 1-alpha hydroxylase from the kidney produced 1,25(OH)2 Cholecalciferol = CALCITRIOL
49
Do most foods contain vitamin D3?
Yes, but very low content
50
What is required to initiate the reaction scheme of making calcitriol?
exposure of skin to sunlight
51
What does D3 deficiency lead to?
rickets and osteomalacia
52
What does calcitriol play a key role in?
calcium metabolism
53
What are bile salts a major breakdown product of?
cholesterol and accounts for about half of the 800mg of cholesterol made each day by the liver
54
What are the names of the bile salts which are synthesised from cholesterol?
Cholesterol is converted by a series of reactions into the primary bile salt glycocholate and also taurocholate.
55
What do lipoproteins solve the problem of?
transporting hydrophobic molecules in an aqueous environment
56
How would you describe the anatomy of a lipoprotein?
Phospholipid monolayer containing cholesterol and apoproteins
This surrounds a core of cholesterol esters and triacylglycerols
The cholesterol within the core has acyl chains so that they can be packed more closely together (cholesterol esters)
57
Hoe are cholesterol esters synthesised?
They are synthesised in the plasma from cholesterol and the acyl chain of phosphatidylcholine (lecithin) via a reaction catalysed by lecithin cholesterol acyltransferase (LCAT)
58
What is the life cycle of VLDL, IDL, HDL and LDL?
VLDLs are synthesised in the liver and released into the circulation.
HDLs are synthesised in the liver and small intestine and take up lipids and cholesterol from tissues back to the liver.
IDLs are formed by triacylglycerols removal from VLDLs.
LDLs are formed by cholesterol ester transfer from HDL to IDL.
*LDL+ macrophage= fatty foam cell
59
What is HDL?
Cholesterol which functions to take cholesterol away from the peripheral tissue back to the liver for use or disposal - helps to lower total serum choleterol
GOOD cholesterol
60
What does prolonged levels of LDL lead to?
atherosclerosis (hardening of arteries)
61
What do LDLs do?
They transport cholesterol which has been made in the liver to the peripheral tissues - more than 40% weight is cholesterol esters
BAD cholesterol
62
What do statins do?
reduce LDL levels and therefore reduce cholesterol levels
63
Are HDLs or LDLs visibly bigger?
LDL, they are 42% cholesterol esters
HDL are 20% cholesterol esters and half the size of LDL
64
Do you understand the summary of lipoprotein transport pathways diagram?
65
What is reverse cholesterol transport?
When cholesterol is transported back to the liver by the actions of HDL
66
Describe the pathophysiology of hypercholesterolaemia?
patients with severe familial hypercholesterolaemia (FH) lack functional LDLRs. .
67
How is familial hypercholesterolaemia inherited?
as a monogenic dominant trait
68
What is the difference between individuals who carry a single copy rather than both copies of the mutant gene involved in FH?
* Individuals who carry a single copy of a mutant gene (homozygous FH) have serum cholesterol levels 2-3 times > than normal and are susceptible to atherosclerosis in middle age.
* Individuals with both copies of a mutant gene are severely affected. Their serum cholesterol levels are 5 times > than normal and severe atherosclerosis and coronary infarcts may occur in adolescence.
69
What are some symptoms of FH?
Orange-yellow xanthomas lying superficially over the knees, wrists, and hands arise from the deposition of plasma LDL-derived cholesterol into macrophages of the skin.
Deposition of LDL derived cholesterol in the coronary arteries can lead to their occlusion and myocardial infarction. Cholesterol rich plaques block the arteries.
70
How is hypercholesterolaemia treated?
Using Resins and HMG-CoA Reductase Inhibitors
71
What is the structure of a LDL receptor?
72
What is an example of a HMG-CoA-Reductase inhibitors?
Statin e.g., lipitor, crestor
Lipitor is one of the best-selling pharmaceutical in history
73
What are the steps of receptor mediated endocytosis of LDL?
LDL binds to LDL receptors on plasma membrane
Endocytosis- clathrin-coated vesicles containing LDL and LDLR
Uncoating
Fusion with endosome
then 2 paths...
Transfer to lysosome
budding odd of transport vesicle
from budding of transport of vesicle...
return of LDL receptor to plasma membrane
74
What are the different classes of familial hypercholesterolaemia from the mutations in the LDLR gene?
75
How do resins work as a medication to contain hypercholesterolaemia?
Resins bind or sequester bile acid-cholesterol complexes preventing their reabsorption by the intestine.
76
What do fats need in order to be made soluble?
They need to be emulsified by bile
77
What does the emulsification of large fat droplets result in?
The formation of micelles
78
How do emulsified fat droplets form micelles?
Pancreatic lipase breaks down the triglycerides which have been emulsified into Free Fatty Acid and Monoglycerides
79
Once pancreatic lipases have digested the emulsified fats, what happens next?
The free fatty acids and monoglycerides leave the micelle and enter into the enterocytes of the small intestine
80
What happens to FFAs and MGs in the enterocytes of the mall intestine?
They reform Triglycerides
81
what forms inside the golgi of the enterocytes?
The fatty triglyceride globules combine with proteins to form chylomicrons
82
Once the chylomicrons are extruded from the enterocyte what happens to them?
They enter into a lacteal and lymph in the lacteal transports chylomicrons away from the intestine
83
After the chylomicron has left the enterocyte of the small intestine, what happens to it on the way to the liver?
The chylomicron starts making its way to the liver and picks up Apoproteins from HDL
84
What is the benefit of apoproteins binding to the chylomicron after it has left the enterocyte?
The chylomicron can bind to lipoprotein lipase which can metabolise the triglyceride component into free fatty acids and the glycerol
85
What are the free fatty acids and glycerol used for?
Adipocytes - storage
skeletal muscle- generate energy
86
What happens to the chylomicron remnants?
They are sent back to the liver
87
Where are LDL sourced from and what is their role?
IDL- cholesterol transport
88
What is the life cycle of chylomicrons?
smaller chylomicron thingy=> remnants of chylomicron
FFA=> free fatty acids
