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GI > Cholesterol > Flashcards

Cholesterol Flashcards

1
Q

VLDL =

A

Triacylglycerol / 5

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2
Q

Where is cholesterol synthesized?

A

In the cytosol of all cells but mostly in liver, intestine, adrenal cortex, and reductive tissues

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3
Q

Function of cholesterol

A
  • structural component of membranes

- precursor of bile salts, steroids, vitamin D

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4
Q

What are the main structural components of cholesterol?

A
  • 4 fused rings
  • hydrocarbon tail
  • OH group on C-3
  • Double bond at C5-C6
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5
Q

Where does de novo synthesis of cholesterol occur?

A

Liver and intestine

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6
Q

What is the source of carbon atoms for cholesterol?

A

Acetyl-CoA

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7
Q

What is the major cofactor in the synthesis of cholesterol? How many are used up?

A

2 NADPH

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8
Q

Which enzyme is responsible for the rate limiting step in the synthesis of cholesterol? What is the product of this step?

A

The step is catalyzed by HMG-CoA reductase. The product is Mevalonic acid

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9
Q

What are the two enzymes responsible for the esterification of cholesterol?

A

ACAT - There’s A CAT in the liver

LCAT - For HDL, in order for it to be packaged into HDL from the peripheral tissues.

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10
Q

In order to maintain homeostasis, what does the body do when there is excess cholesterol?

  • In other words, what are the feedback mechanisms
A
  • too much cholesterol Activates ACAT to make more cholesterol esters, which inhibits The uptake into cells.
  • reduces the level of HMG-CoA reductase through proteolysis (SREBP)
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11
Q

What two hormones regulate cholesterol synthesis? How do they do this? Is this short term or long term?

A

SHORT TERM

  • Insulin causes an increase in HMG-CoA activity by dephosphorylating HMG. CoA Reductase
  • glucagon causes a decrease in HMG-CoA activity by using AMPK to phosphorylates HMG CoA Reductase
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12
Q

SREBP2

A

It senses the concentration of cholesterol in the ER membrane. When the concentration of cholesterol gets too low, vesicles containing SREB2 pinch off of the ER membrane and head to the Golgi apparatus. SREBP2 is then cleaved and the N-terminal segment moves into the nucleus and enhances transcription of many genes including HMG-CoA reductase and LDL-receptors.

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13
Q

Statins

A

Statins are used to reduce the risk of heart disease. It does this by targeting HMG CoA reductase. Statins are analogs of HMG-CoA, the precursor that HMG-CoA Reductase acts on. Therefore, they fight to bind with HMG CoA Reductase and less cholesterol is made.

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14
Q

What is statins affects on LDL?

A

Because there is less cholesterol synthesis in the liver, the liver retrieves cholesterol from lipoproteins that are circulating around the body. Therefore, there is less circulating cholesterol in the body but the homeostasis is restored in the liver. This is accomplished by up regulating the quantity of LDL receptor molecules on hepatocytes in the liver.

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15
Q

Xanthoma

A

Consequence of hypercholesteremia. It is a cutaneous deposition of lipidosis.

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16
Q

Smith-Lemli-Opitz Syndrome (SLOS)

A

Mutation in DHCR7, which is involved in the production of cholesterol. Therefore, not enough cholesterol is made.
The consequences of this are:
- microcephaly, ptosis, broad nasal bridge, upturned nose, micrognathia (small jaw), cleft palate.
- short thumbs, polydactyly, syndactyly of the second and third toes.

Mnemonic - SLOS IS NOT enough cholesterol

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17
Q

Lipoprotein structure

A

Surface - amphipathic lipids with phospholipids and unesterified cholesterol. Also have proteins on the surface.
Anhydrous core - Triacylglycerides and cholesterol found in the anhydrous core

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18
Q

Apolipoprotein

A

They bind lipid in the blood in order to form lipoproteins. The term “apo” means that it is in it’s lipid-free form.

  • They act as recognition sites or ligands for receptors
  • act as structural components
  • act as activators or coenzymes for enzymes involved in lipid metabolism
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19
Q

Which lipoprotein has the Highest proportion of Protein?

A

HDL because if you just remember that it is the highest density then you will remember that it has the highest proportion of proteins.

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20
Q

What are the two Basic phases Of lipoprotein metabolism?

A

1) Processing - in which lipoproteins undergo changes in composition of both core and surface components while in transit in the blood, thus converting them into their remnant form.
2) Clearance - cleared from the blood via a receptor-mediated endocytic process in the liver as well as other tissues.

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21
Q

Where are each of. The 4 types of lipoproteins made?

A

Chylomicrons — intestine
VLDL - liver
LDL - in circulation by the breakdown of IDL
HDL — liver

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22
Q

How does Dietary cholesterol get into chylomicrons and into the liver?

A

Firstly, dietary cholesterol is only found in foods derived from animals. Once in the intestine, dietary cholesterol esters are hydrolyzed, along with other sterols and they enter a micelle with bile salts, fatty acids, and monoglycerides. Epithelial cells from the jejunum then take up sterols via binding to NPC1L1 followed by endocytosis. Then the epithelial cells release all of their sterols other than cholesterol. Then the cholesterol and other cholestoryl esters are incorporated into chylomicrons and they enter the liver.

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23
Q

What are the 3 lipoproteins found on HDL? WHat do they do?

A

Apo C-II - Lipoprotein lipase activator
Apo C-III - Lipoprotein lipase inhibitor
Apo E - ligand for a receptor mediated clearance of remnants of lipoproteins such as chylomicron remnants or VLDL by the liver.

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24
Q

What are the two triglyceride degrading enzymes?

A

Lipoprotein Lipase

Hepatic Lipase

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25
Q

Lipoprotein Lipase

A

It is an extracellular protein found on the walls of blood capillaries anchored to the endothelium. It interacts with the chylomicrons or VLDL to hydrolyze Triacylglycerol to free fatty acids plus glycerol. About 80% of the FFAs are transported to the tissues (heart, adipose, muscle) and 20% goes to the liver. If the FFAs are not used immediately then they are picked up by albumin and circulate through the body.
- Requires ApoC-II as a cofactor

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26
Q

Hepatic Lipase

A

1) It has phospholipase activity but for our concerns currently, it also has triglyceride hydrolase activity. It completes the final processing of chylomicron remnants
2) It hydrolyzes triglycerides in the final processing of IDL–>LDL in order to make FFAs from triglycerides. It is synthesized by hepatocytes and is present primarily on liver endothelial cells.
3) It also participates in the conversion of HDL2 to HDL3.

  • does not need apoCII
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27
Q

How dietary cholesterol metabolized using chylomicrons?

A

As we said earlier, dietary cholesterol is taken up by epithelial cells of the jejunum via binding of NPC1L1 followed by endocytosis. Intestinal cells use “Microsomal triglyceride transfer protein (MTP)” to assemble chylomicrons from Apolipoprotein B-48, triglycerides, phospholipids, cholesterol, and cholestoryl esters. The chylomicrons are then exported into the lymphatic system and from there reach the subclavian vein via the thoracic duct. Once in the blood, chylomicrons gain ApoC-II and Apo E mostly from HDL. Through removal of triglycerides by lipoprotein lipase, chylomicrons become chylomicron remnants, thus making them small enough to fit into the Space of Disse in the liver. Then Hepatic Lipase removes more triglycerides. ApoE then binds to “LDL receptor mediated protein 1 (LRP1)” on hepatocytes and the remnants enter via endocytosis. Lysosomes then degrade the chylomicron remnants.

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28
Q

How long is the half life of a chylomicron?

A

In the order of. Minutes

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29
Q

How long is the half life of a VLDL?

A

On the order of hours

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30
Q

What percentage of a VLDL is lipid?

A

90% lipid

10% protein

31
Q

Where is VLDL synthesized? How?

A

Liver - it gets fatty acids either from carbohydrates or from circulating in the blood and then esterifies them to create triglycerides. The VLDL will have on it already ApoB-100, and varying amounts of ApoE and ApoC-II. Later, more ApoE and ApoC-II will be donated to them. Then, something called LPL comes along in order to degrade TAGs in the VLDL. This results in fatty acids being delivered to peripheral tissues and adipose tissue. Now, the resultant VLDL-remnant, which is also sometimes called IDL. Approximately half of the VLDL-remnants Are cleared by the liver via ApoE and its receptor. The rest are converted into LDL. This conversion from IDL–>LDL is done through Hepatic Lipase.

32
Q

LDL

A

Made from IDL. It Is responsible for majority of cholesterol transport throughout the body. Half life is on the order of days.

33
Q

Clearance Of LDL

A

1 - 2/3 of the circulating LDL is taken up by the liver via ApoB-100 binding to the LDL receptor
- remember, the amount of LDL receptors being expressed is due to the SREBP2 activity, which is altered by cholesterol concentrations.
2 - The remaining third is taken up by peripheral tissues.

34
Q

PCSK9

A

Reaches LDL receptors and prevents their recycling to the plasma membrane and favors their degradation in lysosomes. This is the response to increased cholesterol.

35
Q

SR-A

A

Can recognize normal and damaged LDL particles and are found on macrophages and some endothelial cells. This leads to the formation of what are called “foam cells”

36
Q

Synthesis of ApoB48

A

This guy originally comes From ApoB100 but there is a change of one base from a Cytosine (C) to a Uracil (U), which causes a nonsense mutation and the transcript to be cut well short. This change from C–>U only occurs in the Intestine, which is why ApoB48 only shows up in the chylomicrons, which are made in the intestine. This short transcript is ApoB48.

37
Q

Reverse Cholesterol Transport Pathway

A

Basically HDL just picks up all of the circulating cholesterol from the tissues and brings it back to the liver, which is why it is called the “good cholesterol”
- Much of the cholesterol synthesis that occurs in the liver comes from HDL returning it to the liver.

38
Q

Where. Does HDL. Come from?

A

Liver and intestine

39
Q

HDL

A

Has ApoA-I, which is synthesized in the liver and intestines and activates LCAT. Also has ApoA-II, which is the activator of hepatic lipase. ApoCII, ApoCIII, and ApoE are all added later.

40
Q

ApoA-I

ApoA-II

A

I - activator of LCAT

II - activator of hepatic lipase

41
Q

CETP - Cholesterol Ester Transfer Protein

A
  • Secreted from the liver. Mainly circulates bound to HDL.
  • Overall effect is a net mass transfer of cholesteryl esters from HDL to VLDL and of triglyceride from VLDL to HDL. Essentially they are trading cholesteryl esters for triglycerides
  • — then, hepatic lipase removes those TAGs from HDL, thus making it much smaller.
  • All of this causes a decrease in the cholesterol content and hence a decrease in the overall size of the HDL particle.
42
Q

Primary vs secondary hyperlipemia

A

Primary would be some sort of genetic defect or environmental factors.
Secondary would be as a result of some sort off metabolic disorder such as diabetes, obesity, hypothyroidism, biliary cirrhosis etc.

43
Q

Hypertriglyceridemia

A
  • Total plasma triglycerides in the fasting state above 150 mg/dl.
  • Usually due to an increase in cylomicrons, VLDL, or both. Either VLDL is formed at a excessively quick rate or chylomicrons ad VLDL are removed at an abnormally low rate.
  • Increased risk of CVD
  • Can cause pancreatitis
  • Can cause xanthomas
44
Q

familial hyperchylomicronemia

A
  • whereas chylomicrons are usually cleared by lipoprotein lipase with ApoC-II as a cofactor, in this disease, there is a pathological presence of chylomicrons after a 12-14 hour of fasting.
  • – This causes a hypertriglyceridemia
  • Clinical features - xanthomas, Libemia retinalis, hepatosplenomegaly, neurological symptoms such as irritability, epigastric pain, pancreatitis.
  • samples of Lipemic plasma develop a creamy supernatant when refrigerated.
45
Q

How to treat a patient with recurrent pancreatitis due to familial hyperchylomicronemia?

A

Cessation of food in order to reduce chylomicrons and VLDL.

46
Q

How to distinguish familial hyperchylomicronemia from Primary mixed hyperlipidemia?

A

Familial - presents in childhood. Deficiency off lipoprotein lipase, ApoC-II

47
Q

Familial dysbetalipoproteinemia

A

Increase in IDL

  • this produces an increase in cholesterol levels as well as Triacylglycerol levels.
  • Cause is thought to be a mutant ApoE, which causes either an overproduction or underutilization of IDL.
  • LDL will not be elevated but perhaps even lowered.
  • symptoms are xanthomas, and increased risk of cardiovascular disease.
48
Q

Familial combined hyperbetalipoproteinemia

A
  • defects in synthesis, processing, or function of LDL receptors.
  • caused by overproduction of VLDL in the liver.
  • autosomal dominant with variable penetrance.
  • Increased VLDL and LDL, depressed HDL.
  • the above causes elevated triglycerol as well as cholesterol Levels.
49
Q

Treatment for Hpertriglyceridemia

A

Life-style modification

Drug treatment - statin, fish oil, fibrate, nicotinic acid (niacin).

50
Q

Steps involved in the formation of an atherosclorotic plaque

A

1) recruitment of monocytes/macrophages to the sub endothelial space and the infiltration of LDLs, which get oxidized. The oxidized LDLs are taken up by the macrophages. This leads to the formation of foam cells. Various cytokines and growth factors are released from these foam cells, which initiates a cascade of events.
2) One such event is the formation of a “fatty streak”. When this happens, there is further recruitment of monocytes/macrophages, as well as smooth muscle proliferation, collagen synthesis, and elastin fiber accumulation.
3) “Fibrous lesion” begins to form and continues to extend into the vessel lumen. Smooth muscle cells start to migrate from thhe media through the disrupted internal elastic lamina.
4) a “Complicated lesion” then forms. The endothelial cell layer covering the lesion is lost and the surface of the lesion becomes thrombogenic.

51
Q

Lp(a)

A
  • risk factor for atherosclorosis that is heritable.

- it is a lipoprotein molecule covalently linked by a disulfide bond to ApoB-100

52
Q

Familial hypercholesterolemia

A
  • defective LDL receptor
  • LDL cholesterol is very high but VLDL is normal.
  • increased serum cholesterol but normal TAGs.
  • Increased likelihood of ischemic heart disease.
53
Q

ApoA-1 deficiency

A

If you. Remember, ApoA-1 is the man Apolipoprotein in HDL. If you have a deficiency of it then you will have too little HDL and you can’t get rid of circulating cholesterol.
- In addition to the increased in CAD, patients may have xanthomas and corneal clouding.

54
Q

LCAT deficiency

A
  • Reduced HDL and apoA1 levels. Reduced LDL.
  • elevated TAGS
  • Corneal opacifications.
55
Q

Tangier Disease

A
  • Absence of ABCA1, prevents HDL maturation and cholesterol efflux from peripheral tissues/macrophages to the liver.
  • Orange to yellow discoloration of the tonsils, hepatomegaly, splenomegaly, corneal opacification.
  • neuropathy
  • decrease in HDL and apoA1 levels.
  • ELevated TAGs
  • Decreased LDL
56
Q

Pharmacological Interventions

A

Statins - inhibit HMGCoA reductase
Ezetimibe - inhibits absorption of cholesterol at the brush border membanes in the intestinal lumen and increases the number of LDL receptors on liver.
Nicotinic acid - inhibits mobilization of FFAs from peripheral adipose tissue to the liver.
Bile acid sequestrants - depletes the bile acid pool and disrupts the enterohepatic circulation of bile acids, thus increasing the synthesis of bile acids from cholesterol.
Fibrates - lowers VLDL and increases HDL

57
Q

Total Cholesterol =

A

Total Cholesterol = LDL + HDL + VLDL

58
Q

What happens when you have a genetic abnormality where you make too little cholesterol?

A

SMOS - small head, small jaw, upturned nose, small thumb, polydactyly, ptosis etc.

59
Q

Summarize the life of a chylomicron

A

1) chylomicrons are made in the small intestine
2) They are made with ApoB48 already on them.
3) As they circulate through the blood, they pick up ApoE, ApoC-II, and ApoC-III from HDL
4) Eventually, as they are circulating through the blood, they meet up with lipoprotein lipase, which is an enzyme bound to the surface of capillaries.
5) Lipoprotein lipase is activated by ApoC-II and causes the TAGs of the chylomicrons to be hydrolyzed, which releases fatty acids.
6) Once this happens, the chylomicron shrinks in size due to the lack of TAGs, and it is now called a remnant.
7) ApoC-II is returned to HDL
8) fatty acids go to the various tissues.

60
Q

Where. Does. IDL come from?

A

It is the “remnant” of VLDL just as chylomicron had a remnant.

61
Q

What does ApoE Do?

A

Responsible for the uptake of both chylomicron remnants and IDL back to the liver.

62
Q

What does ApoB100 do?

A

It is the ligand responsible for binding to the LDL receptor and causing uptake of the LDL into the liver.

63
Q

Summary of the endogenous pathway

A

1) VLDL is made in the liver with ApoB100 on it.
2) it circulates through the circulatory system and pics up ApoE, ApoC-II, and ApoC-III from HDL.
3) It eventually meets up with lipoprotein lipase on the capillaries of the circulatory system, which is activated by ApoC-II
4) Lipoprotein lipase causes the TAGs to be degraded into fatty acids, which makes a remnant called IDL.
5) IDL is then converted into LDL via the work of hepatic lipase.
6) LDL returns ApoC-II and ApoE to the HDL.

64
Q

Summary of reverse transport

A

1) HDL is made in both the intestine ad the liver by simply adding a whole bunch of stuff to ApoA-1
2) They use the transporter, ABCA1 to enrich the HDL with phosphatidylcholine, cholesterol, etc. which makes it disc shaped.
3) As soon as cholesterol is added to the HDL, it is esterified by LCAT, which is activated y ApoA-1
4) CETP eventually moves these cholesteryl esters from HDL to VLDL and thus eventually LDL
5) the cholesterol that is left is eventually taken up by the liver via the cell surface receptor SR-B1

65
Q

Total cholesterol ==

A

LDL + HDL + VLDL

VLDL = triacylglycerides/5

66
Q

WHere does VLDL come from ? Chylomicrons?

A

VLDL - lipoprotein derived from the liver
Chylomicrons - Intestines

Mnemonic - I C Ladies V

67
Q

What does Mevalonic acid get converted into?

A

IPP –> Farnesyl –> Squalene –> cholesterol

68
Q

Why is cholestererol esterified?

A

Because it makes it more hydrophobic and thus enables it to e packaged, stored, and transported easier.

69
Q

WHat are the two ways in which cholesterol is cleared from the blood?

A

LDL receptors

SC-A receptor

70
Q

What a would a genetic mutation in lipoprotein lipase or ApoCII do?

A

You wouldn’t be able to get ride of chylomicrons or VLDL so the amount of triglycerides would build up. You would have a creamy supernatant in the blood due to chylomicrons. Eruptive xanthomas occur as well as pancreatitis, which is treated by decreased food intake.

71
Q

WHat would a mutant ApoE cause?

A

An increase in VLDL, IDL, and actually a decrease in LDL because VLDL is not being process properly.
- patients often have xanthomas and increased risk of CVD

72
Q

WHat would happen if you have a. Defective LDL receptor?

A

LDL wouldn’t be degraded and it would stay in circulation. This would cause cholesterol levels to be sky high but VLDL and IDL levels would e normal.

73
Q

What would happen if you had a deficiency in Apo A-1?

A

You would see really low levels of HDL.

- patients may also have corneal opacifications

GI (27 decks)

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