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PHRM 100 – APPP > APPP 23, 26, and 27: Liver Lipoproteins > Flashcards

APPP 23, 26, and 27: Liver Lipoproteins Flashcards

1
Q

What is coronary heart disease (CHD)?

A

occlusion of blood flow through some part of the coronary arteries

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2
Q

What is ischemia?

A

lack of oxygen (blood flow)

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3
Q

What is myocardial infarct?

A

dead heart muscle caused by lack of blood flow

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4
Q

What are the coronary arteries (left and right branches)?

A

supply blood to the heart muscle itself

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5
Q

What happens if the diameter of the lumen of the coronary arteries is reduced by more than 50%

A

ischemia will develop, and the patient will develop tightness or pain the chest

  • note that pain does not always accompany myocardial ischemia (silent ischemia)
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6
Q

What are important risk factors for coronary heart disease?

A

lipid abnormalities

  • elevations in low density lipoprotein (LDL) cholesterol
  • elevated triglycerides
  • low high density lipoprotein (HDL) cholesterol
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7
Q

What are lipid abnormalities also associated with?

A

increased risk of cerebrovascular and peripheral vascular disease

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8
Q

What is severe hypertriglyceridaemia also associated with?

A

risk of pancreatitis (inflammation of the pancreas)

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9
Q

What does CHD present as? (4)

A
  • angina – chest pain that usually comes on during exertion
  • myocardial infarction (MI) – heart attack
  • chronic heart failure
  • sudden death
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10
Q

What is atherosclerosis?

A

process of accumulation of lipid leading to thickening of arterial blood vessels

  • progressive disease beginning with the development of fatty streaks and potentially leading to complicated atherosclerotic plaques that can rupture, set up thrombosis, and occlude the lumen
  • predominantly a disease of arteries (both large and medium-sized) that occurs in areas of high sheer stress – high pressure, high speed blood going by
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11
Q

What is an important risk factor for atherosclerosis?

A

hyperlipidemia

  • good association between serum cholesterol and CHD mortality rate
  • note: this is only ONE of many factors
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12
Q

How does low-density cholesterol (LDL) and high-density cholesterol (HDL) affect atherogenesis?

A
  • LDL: correlates
  • HDL: protective
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13
Q

What are the major fixed risk factors for CHD?

A
  • age – older
  • gender – male
  • family history – genetic defects that influence one’s ability to process lipids in its various forms
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14
Q

Why is CHD present more in males?

A

estrogen is protective because it has multiple beneficial effects on lipids (increases cholesterol removal by the liver) and vascular tone in addition to its antioxidant properties

  • females catch up after menopause
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15
Q

What are the acquired (modifiable) risk factors for CHD? (5)

A
  • hyperlipidemia – especially high cholesterol as shown by high LDL
  • hypertension – accelerates development of atheroma and is more important than cholesterol after age 45, produces increased shear stress on vessel endothelium)
  • diabetes – affects vascular endothelium and lipids
  • obesity
  • smoking – endothelial damage
  • physical inactivity
  • low HDL
  • elevated TG
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16
Q

Are risk factors for CHD synergistic or additive?

A

synergistic

  • 50% of atherosclerosis cannot be explained by standard risk factors (smoking, diet, lifestyle, and high cholesterol)
  • large number of people who develop CHD have the same basic cholesterol numbers as those who do not
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17
Q

What are the functions of cholesterol? (3)

A
  • critical component of cell membranes
  • precursor of aldosterone (important in regulation of blood pressure)
  • precursor of estrogens and androgens, testosterone
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18
Q

Where does the cholesterol we need come from?

A
  • 75% produced within our bodies, mainly from the liver
  • 25% from food
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19
Q

What is HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase?

A

key enzyme in the hepatic synthesis (major source of cholesterol) of cholesterol

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20
Q

What do hepatic LDL receptors do?

A

facilitate the clearance and uptake of plasma LDL cholesterol

  • chief factor controlling plasma LDL levels
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21
Q

What happens when adequate cholesterol becomes available by receptor-mediated uptake?

A

rate of synthesis of LDL receptors is reduced and the critical enzyme (HMG CoA reductase) involved in cholesterol synthesis is inhibited

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22
Q

What are bile acids?

A

the main metabolites of cholesterol that are synthesized exclusively in the liver

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23
Q

Where is cholesterol and bile acids secreted?

A

secreted into the bile, and therefore into the intestine

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24
Q

How much cholesterol and bile are reabsorbed?

A
  • 50% of cholesterol
  • 97% of bile acids
  • returned to liver in portal circulation
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25
Q

What are the 3 main factors that may induce a high plasma cholesterol concentration?

A
  • diet rich in cholesterol, or excessive carbohydrates which may be converted to cholesterol
  • physical inactivity or sedentary lifetyle
  • genetic factors – ie. defect of LDL receptor
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26
Q

What are lipoproteins?

A

soluble complex macromolecules that carry lipids (cholesterol, triglycerides) that are not soluble in blood between gut, liver, and tissues

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27
Q

What are the 5 major types of lipoproteins?

A
  • chylomicrons
  • very low density lipoproteins (VLDL)
  • intermediate-density lipoproteins (IDL)
  • low-density lipoproteins (LDL)
  • high-density lipoproteins (HDL)
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28
Q

What are chylomicrons?

A

carry exogenous dietary cholesterol and triglyceride (compound made of three fatty acids on glycerol backbone – makes up 80-90% of the lipoprotein) packaged in the intestine

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29
Q

What are very low density lipoproteins (VLDL)?

A

carry endogenous cholesterol and triglyceride synthesized in the liver to peripheral tissues

30
Q

What are low-density lipoproteins (LDL)?

A

carry cholesterol to peripheral tissues

  • high levels are linked to increased CHD risk
  • primary target of cholesterol-reducing therapy
31
Q

What are high-density lipoproteins (HDL)?

A

remove cholesterol from cells and macrophages, which is ultimately delivered to the liver either by direct binding of HDL particle to hepatic docking receptors or indirectly by transfer of HDL cholesterol to acceptor lipoproteins

  • high HDL is considered protective against CHD
32
Q

What do chylomicrons mainly carry?

A

triglyceride

33
Q

What do VLDLs mainly carry?

A

triglyceride

34
Q

What do LDLs mainly carry?

A

cholesterol

35
Q

What do HDLs mainly carry?

A

cholesterol

36
Q

What does extracellular lipoprotein lipase (LPL) do?

A

degrades triglyceride into free fatty acids, which are then used for energy by skeletal muscle, OR triglyceride synthesis and storage by adipose tissue and liver

  • present in adipose tissue, skeletal muscle, and heart capillaries
37
Q

What does lipoprotein lipase (LPL) action on chylomicrons do?

A

forms chylomicron remnants

38
Q

What does lipoprotein lipase (LPL) action on triglycerides contained in VLDL do?

A

generates IDL and LDL – the major cholesterol carrier in the blood

39
Q

What is hypercholesterolemia?

A

indicated by elevated LDL

40
Q

Describe LDL particles.

A
  • all LDL particles in plasma are derived from VLDL
  • not all LDL particles are the same – some large and buoyant (LDL pattern A) moving easily through circulatory system, and some small and dense (LDL pattern B) due to the continuing action of LPL and hepatic lipase (4x more likely to cause heart disease)
41
Q

Why are small dense LDL more likely to cause heart disease?

A
  • decreased affinity for LDL receptor
  • longer residence in plasma
  • easier entry into arterial wall
  • greater retention in arterial intima
  • greater susceptibility to oxidation
  • increased endothelial cell dysfunction – increased production of plasminogen activator inhibitor 1 (clot is not dissolved), and TXA2 (increases platelet aggregation)
42
Q

Why is HDL considered protective against the development of atherosclerosis?

A

HDL is secreted mainly from the liver, takes up cholesterol from tissues and plaques, and recirculates (reverse cholesterol transport) it to the liver for excretion in bile

43
Q

Describe the relationship between HDL cholesterol and CHD risk.

A

inverse relationship

44
Q

Describe the relationship between HDL and low HDL and CHD risk

A

compounded risk associated with high LDL and low HDL

45
Q

What are 2 disorders of lipoprotein metabolism?

A
  • hypercholesterolemia – due to elevated LDL
  • hypertriglyceridemia – due to elevated VLDL and/or chylomicrons
46
Q

Where are LDL receptors predominantly present?

A
  • hepatocytes
  • adrenal cells
  • adipocytes
47
Q

Describe the action of LDL receptors.

A
  • bind to LDL particles and endocytose them – rapid (3 minutes)
  • vesicles containing LDL fuse with lysosomal enzymes that degrade LDL
  • LDL receptors are recycled
  • once internalized, cholesterol inhibits HMG-CoA reductase (decreases gene transcription and enzyme activity) and LDL receptors
48
Q

What do mutations of the LDL receptor gene result in?

A

defective or absent LDL receptors, and consequentially high levels of plasma LDL and hypercholesterolemia

49
Q

What is PCSK9 (proprotein convertase subtilisian/kexin type 9)?

A

enzyme that binds to LDL receptor and promotes its internalization and escorts the receptor for lysosomal degradation – prevents recycling of LDL receptor

  • regulates lifespan of LDL receptor
50
Q

How is cholesterol excreted?

A
  • directly by secretion into the bile – almost 50% reabsorbed, and the rest is eliminated
  • conversion to bile acids in liver
  • of the considerable amount of bile acids secreted, 95-97% are taken up again in the lowermost section of the small intestine and recycled back into the liver
51
Q

What are the clinical manifestations of atherosclerosis?

A

depends on the site of lesion

  • coronary arteries: angina pectoris, myocardial infarction
  • CNS: transient cerebral ischemia, stroke
  • peripheral circulation: peripheral vascular disease (intermittent claudification – fatigue and usually pain on walking that is relieved by rest), gangrene
52
Q

What are the 3 layers of the artery wall?

A
  • intima
  • media
  • adventitia
53
Q

Describe the intima layer of the artery wall.

A

consists of an endothelial cell layer and extracellular matrix (where lesions form)

54
Q

Describe the media layer of the artery wall.

A

thickest layer containing predominantly smooth muscle cells

55
Q

Describe the adventitia layer of the artery wall.

A

made up of loose connective tissue, small blood vessels, and nerve fibres

56
Q

What are the main cellular components of artery walls?

A
  • endothelial cells
  • smooth muscle cells
57
Q

Mechanism of Atherosclerosis

What is one of the main risk factors of atheroscleoris?

A

level of plasma cholesterol, particularly LDL-associated cholesterol

58
Q

Mechanism of Atherosclerosis

What is thought to occur to endothelial cells?

A

become dysfunctional or denuded

59
Q

Mechanism of Atherosclerosis

What are the possible sources of injury?

A
  • mechanical (high blood pressure)
  • infection (bacteria, virus)
  • toxins
60
Q

Mechanism of Atherosclerosis

What happens in this ‘response to injury’ hypothesis of lesion formation?

A

small lesions in the vascular endothelium (or an increase in endothelial permeability) allow leakage of blood into the vascular wall

  • then there is an infiltration of plasma lipoproteins, including LDL (initial event in atherosclerosis
61
Q

Mechanism of Atherosclerosis

Describe the mechanism.

A
  1. increased LDL infiltration into the intima following trapping and aggregation (ie. rapid LDL transport into subendothelium with slow LDL transport out) with potential oxidative modification (trapped LDL is exposed to highly reactive oxygen species containing unpaired electrons) yields modified Ox-LDL
  2. modified LDL causes endothelial cell to express monocyte chemoattractant protein (MCP-1)
  • MCP-1 attracts monocytes (phagocytic cells) from the vessel lumen into the subendothelial space in what is one of the very early stages in the development of atherosclerosis
  • monocytes basically migrate along MCP-1 gradient
  • monocytes adhere to the injured endothelium and migrate through into the intima (monocyte transmigration)
  1. modified LDL also promotes differentiation of monocytes into macrophages – start expressing receptors that permit uptake of modified LDL
  2. macrophages release a variety of chemicals including cytokines (ie. tumor necrosis factor alpha)
  3. cytokines activate endothelial cells to express adhesion molecules (ie. vascular cell adhesion molecule – VCAM-1) that bind monocytes, making them available for recruitment of additional circulating monocytes into the intima
  • unlike normal LDL, Ox-LDL is avidly taken up by macrophages and accumulates within them to form lipid-rich foam cells that are the hallmark of atherosclerosis - foam cells (lipid-laden macrophages) and fatty acid streaks (the earliest lesion resulting from accumulation of foam cells and lipid in intima) are eventually formed
  1. engorgment of foam cells causes released of more cytokines and proteolytic enzymes, and eventually cell death (necrotic core)
  • proteolytic enzymes cause degradation of the internal elastic lamina, allowing for smooth muscle cells from adjacent media to integrate into the intima, proliferate, and secrete fibrous connective tissue (ie. collagen) and extracellular matrix (smooth muscle cells change phenotype from contractile cells to synthetic cells)
  • this makes the lesion harder and contributes to the formation of a fibrous cap (which covers a mixture of macrophages, lipid, and cell debris which form a necrotic core
  • the expanding intima pushes against the endothelial wall of the intima and the fibrous cap is very susceptible to rupture (macrophages release proteolytic enzymes that cause a thinning of the fibrous cap) with a host of other events occurring like platelet aggregation and adhesion, thrombosis, and clot formation
  • the rupture of such lesions is believed to be responsible for most causes of unstable angina and acute MI
  • dislodging the clot blocks the artery near the plaque or in a more distal and narrow segment, causing total or near total occlusion
  • if damage to myocardium is severe, pumping action of the heart will be impaired, resulting in congestive heart failure, or if very severe, sudden cardiac death
62
Q

What does HDL inhibit and promote?

A
  • inhibits LDL oxidation to Ox-LDL
  • promotes cholesterol efflux
  • inhibits adhesion molecule expression
63
Q

What is the total cholesterol (TC) to HDL ratio?

A

considered to be more important than HDL levels alone

64
Q

What is the most important (primary) intervention for atherosclerosis?

A

lifestyle modification to minimize risk factors

65
Q

What is the initial treatment for hyperlipidemia?

A

diet, weight reduction, and exercise program

  • however due to poor compliance, patients usually cannot get to their target cholesterol levels
  • intro to drug therapy does not mean non-drug therapy should be discontinued
66
Q

What can symptoms of hyperlipidemia be controlled by?

A

can be controlled by mediations

  • there is evidence that lipid-lowering therapies stabilize and may shrink plaques
67
Q

Control of what conditions is important for hyperlipidemia?

A
  • diabetes
  • hypertension
68
Q

What are some other interventions for hyperlipidemia?

A
  • coronary artery bypass grafting (CABG) – saphenous vein bypass grafting, internal mammary artery bypass grafting
  • balloon angioplasty/stenting
  • thrombolytics (non-surgical)
69
Q

Points to Remember

A
  • 2 primary forms of lipids: triglycerides, cholesterol
  • triglycerides function as energy source and are stored in adipose (fat) tissue
  • cholesterol is used primarily to make steroid hormones, cell membranes, and bile acids
  • lipoproteins transport lipids via blood
  • lipids and lipoproteins participate in formation of atherosclerotic plaques
  • in the heart, plaque formation in coronary blood vessels that supply the heart with needed oxygen and nutrients, reduces lumen diameter of these blood vessels, eventually leading to CHD
70
Q

How should pharmacists counsel patients?

A
  • in addition to cholesterol, contributing risk factors for CAD include high-fat diet, sedentary lifestyle, smoking, obesity, high stress levels, diabetes, and hypertension
  • CAD prevention and treatment aim at decreasing these risk factors to delay disease or decrease progression
  • individuals are encouraged to adopt healthy eating habits (vegetables, fruits, whole-grain cereals, fish, fibre, nuts), 150 minutes of moderate-to-vigorous intensity aerobic physical activity per week, and smoking cessation
  • although serum cholesterol is still considered an important risk factor for CVD, cholesterol consumed in food is now thought to play a relatively insignificant role in determining blood levels of cholesterol (a major shift in the scientific view of cholesterol)
71
Q

What is the cause of the most acute coronary syndromes?

A

thrombosis of a disrupted atheroma

PHRM 100 – APPP (23 decks)

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