Biochemistry > Week 8: Cholesterol > Flashcards

Week 8: Cholesterol Flashcards

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1
Q

What does cholesterol served as a precursor for?

A
  1. Steroid hormones
  2. Bile salts
  3. Vitamin D
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2
Q

Why isn’t cholesterol a dietary requirement?

A

It can be made de novo by most cells

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3
Q

What is the importance of the liver in regards to cholesterol?

A

Regulates cholesterol homeostasis

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4
Q

Where does cholesterol come from before the liver?

A
  1. Dietary intake
  2. De novo synthesis
  3. Delivery from extrahepatic tissue
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5
Q

How is cholesterol eliminated from the liver?

A
  1. Unmodified cholesterol goes into bile to be converted into bile salts
  2. Salts or secreted into the intestinal lumen
  3. Inserted into the plasma membrane
  4. Used as a lipoproteins components to carry lipids
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6
Q

What is amphipathic?

A

Both hydrophobic and hydrophillic

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7
Q

Describe the characteristics of cholesterol?

A
  1. Amphipathic
  2. 3 six membered and 1 five membered fused rings
  3. Hydroxyl C-3, Side chain C8-10 at C-17
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8
Q

What is the major sterol of animal tissue?

A

Cholesterol

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9
Q

Where does cholesterol synthesis occur?

A

Cytosol and SER

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10
Q

What are the steps of the eukaryotic cholesterol biosynthesis?

A
  1. 3 Acetates (2-C) condense into mevalonate (6-C) = Requires 12 NADPH
  2. Mevalonate converted into isoprene (5-C) = 18 ATP
  3. 6 isoprenes polymerize to form a 30C linear squalene (activated isoprene) = Requires 1 NADPH
  4. Squalene cyclizes to form the 4 rings called cholesterol = Requires 1 NADPH
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11
Q

How much energy is required to make acetyl-coa to cholesterol?

A

14 NADPH and 18 ATP

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12
Q

How do you synthesize mevalonate from acetyl-coa?

A
  1. 3 Acetyl-Coa thiolased into Acetoacyl-coa
  2. Acetoacyl-coa is synthesized by HMG-Coa to form HMG-Coa
  3. HMG-Coa used HMG-CoA reductase and 2 NADPH to form mevalonate
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13
Q

What enzyme would be the drug target for lowering cholesterol?

A

HMG-CoA reductase

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14
Q

What is the rate-limiting step form cholesterol synthesis?

A

HMG-CoA reducase

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15
Q

What are activators of cholesterol synthesis?

A

Insulin

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16
Q

What are the inhibitors of cholesterol synthesis?

A

Glucagon, Statin drugs, Epinephrine

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17
Q

What are the fates of cholesterol after synthesis?

A
  1. Can be converted to cholesterol esters and stored in intracellular lipid droplets
  2. Converted in bile acids and salts
  3. Adrenal cortex
  4. Reproductive tissues
  5. Incorporated into plasma membrane
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18
Q

What is responsible for making steroid hormones by nuclear receptors?

A

Liver

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19
Q

What steroid helps with penetration and development of mammary tissue?

A

Progesterone

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20
Q

What steroid helps with liver metabolism, immune function, and adaptation to stress?

A

Cortisol

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21
Q

What steroid helps with ion transport in kidneys and BP regulation?

A

Aldosterone

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22
Q

What steroid hormone helps with development of male reproductive organs?

A

Testosterone

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23
Q

What steroid hormone helps with development of female reproductive organs?

A

Estradiol

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24
Q

What is the sunshine vitamin?

A

D

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25
What is caused due to a Vitamin D deficiency?
Rickets
26
What is the active form of vitamin D the binds to receptor that affects gene expression?
Vitamin D3
27
What kind of process is bile acids and salts synthesis?
Anabolic requiring NADPH
28
Where are bile acids and salts produced?
Liver
29
Where are bile acids and salts stored?
Released into the duodenum and stored in the galbladder
30
Where are lipid emulsified?
Ileum
31
How does cholesterol convert into bile salts?
Emulsification
32
What is chloestyramine?
Bile acid squestrant that bind to bile salts in intestine preventing reabsorption and promotes excretion that can lower cholesterol levels
33
What other bile acid sequestrant can increase excretion?
Dietary fiber
34
Describe bile acid synthesis
1. Cholesterol is converted in cholate 2. Cholate (bile acid) modified into more water soluble bile salts (taurocholate and glycocholate) 3. Taurine comes from diet or Cys and Met 5. Glycine would help glycocholate synthesis 6. Bile salts are secreted into small intestine from bile duct
35
What is the most abundant bile acid in humans?
Cholate
36
Why is plasma cholesterol in esterized form?
The ester from a joined fatty acid makes it more hydrophobic than cholesterol preventing them from entering membranes
37
How are cholesteryl esters transported?
Lipoproteins
38
What is a lipoprotein?
Lipid-protein complex that vary in size, density, and composition help transport fats to organs
39
Describe the composition of a lipoprotein?
Spherical core of neutral lipids coated with unesterfied cholesterol, phospholipids and apolipoproteins
40
What are apolipoproteins?
Specify the site of peripheral uptake of the lipoproteins by mediating the binding of receptors. Protein part of the lipoprotein
41
How are lipoproteins classified?
1. Name based on sedimentation (density) 2. Composition of components
42
Which lipoproteins have high levels of TAGs?
Chylomicrons and VLDL
43
Which lipoproteins has high levels of protein?
HDL
44
Which lipoprotein has high levels of esterfied cholesterol?
LDL
45
What are the compositions of a plasma lipoprotein netural core?
TAG, Cholesterol esters
46
How are TAGs and CEs obtained?
1. Diet (exogenous) 2. De novo (endogenous)
47
What surrounds the core of a plasma lipoprotein?
1. Apolipoproteins 2. Phospholipid 3. Free cholesterol 4. Oriented polar portions facing the surface 5. Particle soluble in aqueous solution
48
What are the functions of apolipoproteins?
1. Serve a structural role 2. Act a ligands for lipoprotein receptors on cell surfaces 3. Guide the formation of lipoproteins 4. Serve as activators or inhibitors of enzymes of lipoprotein metabolism
49
What apolipoprotein activates LCAT and interacts with ABC transporter?
ApoA-1
50
What apolipoprotein binds to LDL receptors?
ApoB-100
51
What apolipoprotein activates lipoprotein lipase?
ApoC-II
52
What apolipoprotein triggers clearance of VLDL and chylomicron remnants?
ApoE
53
What is the lipoproteins associated with ApoA-1?
HDL
54
What is the lipoproteins associated with ApoB-100?
VLDL, LDL
55
What is the lipoproteins associated with ApoC-II?
Chylomicrons, VLDL, HDL
56
What is the lipoproteins associated with ApoE?
Chylomicrons, VLDL, HDL
57
How do meal and fasting states affect chylomicron sizes?
High fat meals: large particles Fasting: small particles
58
Where are chylomicrons assembled?
SER
59
What is the function of chylomicrons?
Move dietary lipid through the intestinal mucosa to the lymphatic system and then enters the blood
60
What is transported in a chylomicron?
1. 90% TAGs 2. Cholesterol 3. Fat-soluble vitamin
61
What is the largest and least dense lipoprotein?
Chylomicrons due to lipids
62
How are chylomicrons formed?
1. TAGs are emulsified by bile acids and pancreatic lipases cleaves them into monoacyl glycerol and free fatty acids 2. TAGs are reformed in the mucosa and packaged in chylomicrons 3. Chylomicrons are exported to lymphatic system then circulatory system to peripheral tissues
63
How are dietary cholesterols absorbed?
1. Dietary cholesterol is imported to a enterocyte by a NPC1L1 protein transporter 2. Cholesterol is packaged into a chylomicron and taken to the liver
64
What does Ezetimibe (Zetia) due?
Blocks NPC1L1 to prevent uptake of dietary cholesterol
65
What is a chylomicron remnant?
1. Chylomicrons shrink due to peripheral tissues removing the TAGS from lipoprotein 2. Remnant is enriched in cholestrol 3. CE > C > TAG
66
Where does chylomicron remnants go?
Taken up by the liver by endocytosis and broken down by lysosomes into aa's, free cholesterol, fatty acids
67
How are VLDL formed?
1. Liver creates TAGs from excess carbs and protein 2. TAG synthesis uses acetyl-coa and proteins to generate palmitic acid in cytosol 3. Palmitic acid is converted to TAGS and exported as VLDL particles 4. Particles are assembled in the ER and packaged in Golgi 5. Exported to circulatory system 6. Hepatocytes synthesize cholesterol from acetyl-coa that is also packaged into VLDL 7. VLDL deliver TAGs and CE to tissues
68
What does a VLDL particle consist of?
1. Apolipoprotein 2. Endogenous TAGs 3. Phospholipids 4. CE
69
What apolipoproteins are in VLDLs?
ApoB-100 and ApoE for uptake in liver Apo-CII that activate lipoprotein lipases
70
Where is VLDL secreted?
Blood by the liver and transported to muscle and adipose tissue
71
What occurs when VLDL comes across lipase?
1. Catalyze the release of free FA from TAGS 2. Becomes smaller and denser by donating TAGs to HDL 3. Transformes to LDL
72
What is an IDL?
1. VLDL delivers Tags to peripheral tissues where it would decrease size and be cholesterol enriched 2. Binds to LDL receptor by ApoB-100 3. Breaks down by liver and converted to LDL
73
What is LDL?
1. Produced by removal of TAGs from VLDL 2. More enriched in CE and cholesterol 3. Main carriers of cholesterol from liver 4. Taken up into cells by LDL receptors by ApoB-100
74
What are the components of HDL?
ApoA-1 Phospholipds
75
What is the purpose of HDL?
Take up cholesterol from peripheral tissues and take it back to the liver as CE
76
What is LCAT?
Enzyme that converts cholesterol into CE
77
What is in the core of HDL?
CE
78
What is reverse cholesterol transport?
1. HDL particles transport excess cholesterol from cells to liver 2. Where its used to make bile salts or steroid
79
Why is high HDL concentrations considered protective?
It has the ability to extract cholesterol and deliver it back to the liver
80
Describe cholesterol uptake by receptor-mediated endocytosis
1. LDL receptor moves to the the plasma membrane by the secretory vescicels 2. LDL receptor bind to the ApoB-100 on LDL, endocytosis occurs 3. LDL is in a endoscope 4. LDL receptor disassociates and return to cell membrane 5. Lysosome fuses with endosome 6. Lytic enzymes degrade apoB-100 and CE, releasing aa, fatty acids, and cholesterol 7. Cholesterol is stored in lipid droplets and used for steroids, plasma membrane, or bile salts
81
What occurs when there is a high level of Cholesterol?
1. Decrease activity of HMG-CoA reductase 2. Decreases LDL receptors on cell surface
82
How are LDL receptor numbers regulated?
Cholesterol content of a cell
83
What occurs when ACAT activity increases?
1. Low HMG-CoA reductase 2. Increased concentration of intracellular cholesterol 3. Low numbers of LDL receptors
84
Where is a LPL synthesized?
mucles, heart, adipose tissue
85
What is the function of a LPL?
1. Attaches to the endothelium of adjacent blood capillaries 2. LPL catalyzes TAG hydrolysis carried by chylomicrons and VLDL 3. TAG catabolism converts chylomicrons into remnants and VLDL to LDL
86
How does insulin stimulate LPL expression?
Moves lipids in VLDL to adipose for storage
87
What is the role of hepatic lipases?
1. Mediates the hydrolysis of TAG and phospholipids in IDL and LDL leading to smaller particles 2. IDL -> LDL 3. LDL -> smaller LDL 4. Hydrolysis of TAG and phospholipids in HDL
88
Describe the exogenous pathway to make chylomicrons
1. In the intestine dietary lipids and cholesterol are hydrolyses by FA and monoacylglyceral by lipases and emulsified by bile salts 2. Chylomicrons are made from TAG and CE in the ER of small intestine 3. Chylomicrons are secrete into lymph to blood 4. Delivers nutrients to muscle and adipose 5. LPL in muscle and adipose are high levels and transported to capillaries 6. ApoC-II activated LPL forming free FA and glycerol used as fuel 7. Chylomicron remnants are taken up to the liver 8. Remnants release cholesterol and degrade by lysosomes 9. Cholesterol becomes VLDL or bile acids
89
What anchors LPL to capillary endothelium?
GPI
90
Where does the the FA go once released by the LDL?
Adipocytes converted them to TAG and stores them in lipid droplets Muscles use them as energy
91
Describe the endogenous pathway to form VLDL and LDL
1. TAG and CE are transferred in ER to ApoB-100 to produced VLDL 2. VLDL is transported to tissue and TAG is hydrolyzed by LPL 3. LPL is activated by ApoC-II on VLDL 4. FAs are released (fasted) and used as fuel or storage (fed) 5. LPL enzyme removes TAG from VLDL producing IDL (enriched with CE) 6. Remaining TAG in IDL is removed by circulation of liver 7. IDL binds to LDL receptor and goes into liver 8. Hepatic lipase hydrolyzes IDL to LDL by decreasing TAG content
92
How is the endogenous pathway of VLDL and LDL regulated?
1. Plasma LDL 2. Number of LDL receptors
93
Describe the endogenous pathway of HDL
1. ApoA-1 is synthesized by liver joins phospholipids to form HDL 2. Protein rich and contains the enzyme LCAT 3. LCAT synthesizes FA and CE 4. HDL removes cholesterol from tissues back into the liver
94
What is atherosclerosis?
Hyperlipidemia causing an elevation of lipids in blood
95
What occurs by atherosclerosis is progressive?
Plaque forms from lipid accumulation in blood vessel walls
96
What occurs when plaque ruptures?
Myocardial infarction or stroke
97
How does atherosclerosis plaques form?
1. Oxidized LDL sticks to endothelial cells that line arteries 2. Macrophages fill up with oxidized LDL and become foam cells 3. Foam cells accumulate and secrete factors of collagen and migration of smooth cells 4. HDL carries foam cells to liver
98
What are the mechanisms of LDL receptor deficiency?
1. Failure to take up cholesterol bound to LDL particles leading to accumulation and elevation of blood LDL levels 2. Decreased levels of internalized cholesterol leading to elevated activity of HMG-CoA reductase
99
How does statin drugs lower plasma cholesterol levels?
1. Blocking de novo cholesterol synthesis by inhibiting HMG-CoA reductase 2. Increased surface LDL-R levels to increase endocytosis of LDL
100
What occurs when there are low cholesterol levels?
1. Trigger of SREBP 2. SREBP cause the activation of gene transcription of LDL-R gene 3. Increased production of LDL receptors 4. Increase LDL endocytosis
Biochemistry
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