L38 – Abnormal lipid metabolism; atherosclerosis

Question 1

What are the 2 pathways for transportation of lipids by lipoproteins?

Answer 1

Exogenous and Endogenous pathways

Question 2

What is first released in the exogenous pathway?

Answer 2

Mucosal cells in small intestine produce NASCENT CHYLOMICRONS from dietary lipids

Question 3

Describe the nascent chylomicron secreted by small intestine mucosal cells at the start of exogenous pathway?

Answer 3

Contains apo B-48
TAG rich  (TAG > CE, C)

Question 4

What happens to nascent chylomicron in exogenous pathway?

Answer 4

HDL transfer apo C-II and apo E to n. chylomicron

n. chylomicron now has apo C-II, apo E and apo B48

Question 5

What happens to chylomicron in capillaries of tissue in exogenous pathway?

Answer 5

After gaining apo E and apo C-II from HDL >
apo C-II activates lipoprotein lipase (LPL) >
TAG in chylomicron degraded into Fatty acid + glycerol

Question 6

Fate of molecules released from chylomicron in exogenous pathway to tissue?

Answer 6

TAG in chylomicron broken down into FA and glycerol by LPL

FA enter into tissue
Glycerol to liver

Question 7

After TAG break down in chylomicron at tissue in exogenous pathway, what happens to chylomicron?

Answer 7

Apo C-II is returned to HDL (previous given by HDL to activate LPL)

Becomes Chylomicron Remnant (CE-rich)

Question 8

What apolipoproteins does chylomicron remnant contain?

Answer 8

Only apo E and apo B48

Question 9

What happens to chylomicron remnant in exogenous pathway?

Answer 9

Chylomicron remnants bind through apo E to specific

receptors on liver > endocytosed

Question 10

In the endogenous pathway , what is secreted to start the transport?

Answer 10

Liver secretes NASCENT VLDL (unlike exogenous where n. chylomicron is secreted)

Question 11

Describe nascent VLDL in endogenous pathway.

Answer 11

TAG-rich

contain primarily endogenously synthesized lipids, apo B-100

Question 12

What happens to nascent VLDL to turn it into mature VLDL in endogenous pathway?

Answer 12

HDL transfers apo C-II, apo E to nascent VLDL via cholesteryl ester transfer protein (CETP)

Question 13

Describe mature VLDL.

Answer 13

TAG rich

apo B-100, apo E, apo C-II

Question 14

What happens to mature VLDL in exogenous pathway?

Answer 14

Extracellular LPL activated by apo C-II on mature VLDL at capillaries > degradation of TAG into FA and glycerol

Question 15

Fate of TAG breakdown by LPL in endogenous pathway?

Answer 15

TAG > FA + glycerol

FA enter into tissue
glycerol to liver

Question 16

What processes turns mature VLDL to LDL in endogenous pathway?

Answer 16

mature VLDL return apo C-II and apo- E to HDL

No longer TAG-rich
CE- rich, only apo B-100

Question 17

What happens to LDL in endogenous pathway?

Answer 17

LDL binds through apo B-100 to receptors on liver OR extrahepatic tissue to be endocytosed

Question 18

What is the difference in the ultimate fate of lipid transport between endogenous and exogenous pathways?

Answer 18

Endogenous > LDL to either liver or extrahepatic tissue

Exogenous > Chylomicron remnant to liver

Both use different apo. to enter cells (LDL= apo B100, CR= apo E)

Question 19

What forms nascent HDL? *

Answer 19

Free apo A1 + excess cholesterol from peripheral cell via ABCA1 channel

Question 20

How does nascent HDL pick up even more cholesterol? *

Answer 20

from peripheral cells via ABCG1 channel

Question 21

What converts all the cholesterol HDL picks up into internalized Cholesterylester (CE) ? *

Answer 21

LCAT on HDL surface

Question 22

What is the role of HDL?

Answer 22

Bring cholesterol from peripheral tissue to liver

Question 23

What receptor is important in the uptake of HDL to liver and steroid hormone-producing tissue? *

Answer 23

SR-B1 receptor

Question 24

What receptor is for transfer of cholesterol to VLDL, LDL, IDL to move into liver? *

Answer 24

CETP channel

Question 25

What is the role of Apo B-100?

Answer 25

Found on VLDL, LDL (and IDL) For LDL receptor binding upon returning to liver/ enter extrahepatic tissue in endogenous pathway

Question 26

What is the role of apo B-48?

Answer 26

Found in n. chylomicron, chylomicron, chylomicron remnant For secretion of chylomicron (and VLDL)

Question 27

What is the role of apo E?

Answer 27

Found on chylomicrons, HDL, LDL, VLDL For chylomicron remnant receptor binding to uptake to liver in exogenous pathway

Question 28

What is the role of apo A1 (and A2)? *

Answer 28

for formation of HDL (and chylomicron) Act as LCAT activator on HDL > turn TAG into internalized CE

Question 29

Role of apo C-II?

Answer 29

Found in HDL, CHylomicron, VLDL (and IDL) For activation of Lipoprotein lipase to break down TAG into FA and glycerol

Question 30

What is used in the centrifuge of blood to separate blood into its components?

Answer 30

Centrifuge blood with jelly (lighter than red cells, heavier than serum) > separate blood into serum and RBCs

Question 31

Which bit of centrifuged blood is used to assess lipid abnormalities?

Answer 31

The serum

Question 32

What is the colour of serum in fasted vs lipemia ?

Answer 32

Fasted = clear Lipemia = cloudy

Question 33

What 2 tests can be done to test for cholesterol in blood? *

Answer 33

Standing plasma test | Lipoprotein electrophoresis

Question 34

What is Type I phenotype in Frederickson classification? Rare or not? What is in the blood? *

Answer 34

Chylomicronaemia Rare Accumulation of chylomicron in blood, very high TAG, cholesterol normal or slightly high

Question 35

What causes Type I phenotype? *

Answer 35

Defective apo C2 (main reason) LPL not activated by defect apo C-II, chylomicron not converted to c. remnant, accumulate in blood

Question 36

What is the appearance of serum in Type I phenotype? *

Answer 36

Cream layer chylomicron form distinct opaque band Infranatant

Question 37

What is one Type IIa phenotype? *

Answer 37

familial hypercholesterolaemia

Question 38

What is defective to cause Type IIa ? Common or not? *

Answer 38

Deficient/ defective LDL receptor in endogenous pathway LDL clearance into liver is hampered > accumulate of LDL Most common

Question 39

Appearance of serum of Type IIa?

Answer 39

Clear (LDL cant be seen)

Question 40

What causes type IIb phenotype? *

Answer 40

Deficient/ defective LDL receptor AND Apo B-100 B-100 is found in LDL, VLDL, IDL Defect leads to accumulation of all three

Question 41

Appearance of serum in type IIb? *

Answer 41

Turbid to opaque

Question 42

What is one type III phenotype?

Answer 42

familial dysbetalipoproteinemia

Question 43

What is defective in type III? Common or Rare?

Answer 43

Apo E present in chylomicron, chylomicron remnant, VLDL and IDL IDL and Chylomicron remnant accumulate Very rare

Question 44

Appearance of serum in type III?

Answer 44

THIN cream layer (unlike type I thick cream) Infranatant

Question 45

Name one type IV phenotype? Common?

Answer 45

Sporadic hypertriglyceridemia Very common

Question 46

Cause of type IV?

Answer 46

unknown Very high VLDL levels Could be eating habits, diabetes, metabolic defects

Question 47

Appearance of serum?

Answer 47

No cream Turbid to opaque

Question 48

Name one type of Type V phenotype?

Answer 48

familial hypertriglyceridemia

Question 49

What causes type V?

Answer 49

low LPL very high Chylomicrons and VLDL rare

Question 50

Appearance of type V serum?

Answer 50

Cream layer Infranatant

Question 51

What 2 genes are defective in Type IIa phenotype?

Answer 51

ARH and PCSK9

Question 52

Which type of lipemia phenotype has no clinical findings/ subsequent diseases?

Answer 52

Familial hypertriglyceridemia Type IV or V

Question 53

Except for familial hypertriglyceridemia, what are the two common clinical findings for lipemia?

Answer 53

Xanthomas | Premature atherosclerosis

Question 54

What is mixed hyperlipidemia?

Answer 54

Both hypercholesterolemia and hypertriglyceridemia

Question 55

What is Hypertriglyceridemia associated with?

Answer 55

(e.g. type IV, V): elevated TAG is associated with increased insulin resistance

Question 56

What is the remedy for Hypertriglyceridemia ?

Answer 56

Diet control

Question 57

What is Hypercholesterolemia associated with?

Answer 57

type II elevated serum LDL-cholesterol contribute to atherosclerosis / formation of atheroma

Question 58

What is the remedy for Hypercholesterolemia ?

Answer 58

drug management

Question 59

Which phenotype is associated with PCSK9 defect?

Answer 59

Type IIa

Question 60

Which lipid is high in plasma in hypocholesterolemia?

Answer 60

LDL Cholesterol rich, apo B

Question 61

Explain action of PCSK9 on LDL regulation

Answer 61

LDL receptor expression is regulated by PCSK9 Normally, PCSK9 complexes with LDL receptor and degrades it Type IIa defect: PCSK9 inhibited > prolong expression of LDL uptake > increase LDL uptake to cells

Question 62

How come increased LDL uptake into cell in hypercholesterolemia (e.g. type IIa phenotype) is bad?

Answer 62

Increased plasma LDL > | LDL is small, infiltrate endothelium by passive diffusion > form atheroma/ lesion of fibrous plaque

Question 63

What is the difference between activated and normal endothelial cells?

Answer 63

Activated endothelium = more permeable, more inflammatory cytokines and leukocyte adhesion molecules Less antithrombotic molecules

Question 64

What is the difference between activated and normal arterial smooth muscle cells?

Answer 64

Activated: more inflammatory cytokines, increase ECM synthesis and migration + proliferation into intima

Question 65

What is the Ultimate complication of atherosclerosis?

Answer 65

Fibrous cap erupt > thrombosis > Stroke, Coronary artery disease, Myocardia infarction

Question 66

Compare how common or rare the phenotypes are?

Answer 66

Type I, III - very rare Type V - rare Type IV - very common Type IIa, IIb - MOST common From rare to common: 1,3,5,4,2