Lipoproteins II

Question 1

Higher levels of PCSK9 result in ____ targeted LDL on hepatocytes. Inhibitors of PCSK9 are used as treatment against _____.

Answer 1

Lower numbers of targeted LDL on liver cell membranes. PCSK9 inhibitors treat hypercholesterolemia.

Question 2

Describe the development of atherosclerosis from LDL in 5 steps.

Answer 2

1. LDL penetrates artery wall from endothelial injury.
2. LDL is oxidized by ROS.
3. Oxidized-LDL is engulfed by macrophages to produce foam cells.
4. Foam cells form a fatty streak near vessel lining.
5. SM cells proliferate on lining = Atherosclerotic plaque

Question 3

List at least 3 factors that can lead to endothelial injury associated with atherosclerosis.

Answer 3

Chemical/oxidative stress, HTN, diabetes, smoking, dyslipidemia.

Question 4

What receptor on the macrophage is associated with the cleanup of Ox-LDL? What is the unique feature about it?

Answer 4

Scavenger Receptor A is not downregulated when intracellular cholesterol levels rise.

Question 5

What type of LDL particle is considered more pro-atherogenic? Define some key features about it.

Answer 5

Small dense LDL (sdLDL) is considered pro-atherogenic. These have less affinity for LDL receptor, easily penetrate the arterial wall and are susceptible to oxidation (to be picked up by macrophages).

Question 6

What is Lp(a) and its significance?

Answer 6

Lp(a) is a heritable risk factor of atherosclerosis that has a disulfide bond to apoB-100 of LDL. It has a kringled shape and is not fully understood (may be linked with accelerated clotting rates).

Question 7

A nonsense mutation of a gene that codes for PCSK9, will result in ______ LDL-cholesterol levels. What is unique about this mutation?

Answer 7

Decreased LDL-C because less PCSK9 = more LDL receptors = less circulating LDL. This mutation lowers the risk of heart disease and is found in certain ethnic groups, such as groups of people in South Africa.

Question 8

Define the Friedewald equation.

Answer 8

This equation is used to calculate LDL cholesterol. Equation:
LDL CE = Total Cholesterol - HDL CE - (TAGs/5)

Question 9

What are the normal reference panels for each, according to the NIH? (Total cholesterol, LDL-C, HDL-C and Triglycerides)

Answer 9

Total cholesterol <200 mg/dL
LDL-C < 100 mg/dL
HDL-C > 40 mg/dL
TAGs < 150 mg/dL (otherwise at risk for metabolic syndrome)

Question 10

What are the relative values of LDL, HDL and TAGs in Dyslipidemia?

Answer 10

In Dyslipidemia, LDL and TAGs increase, HDL decreases. This can be caused by Hypercholesterolemia, Hypertriglyceridemia or Hypoalphalipoproteinemia (high LDL)

Question 11

What is the function of Hepatic lipase and what apolipoproteins are associated with it?

Answer 11

HL (found on liver and endothelial cells) hydrolyzes TAGs and phospholipids. It is associated with Apo A-II.

Question 12

What is the function of Lipoprotein Lipase and what apolipoproteins are associated with it?

Answer 12

LPL (found on endothelial cells) hydrolyzes TAGs from chylomicrons and vLDL to convert them into FFAs and glycerol. It is activated by Apo C-II.

Question 13

What is the function of Lecithin-cholesterol acytransferase and what apolipoproteins are associated with it?

Answer 13

LCAT (located on liver cells) esterifies cholesterol in plasma. It also increases HDL levels. It is activates Apo A1.

Question 14

Where are ApoB100 proteins found and what is their function?

Answer 14

ApoB100 found on vLDLs bind LDL receptors on the liver and endothelial cells for vLDLs to deposit their TAGs and CE.

Question 15

Where are ApoB48 apolipoproteins located and what is their function?

Answer 15

ApoB48 found on chylomicrons bind LDL receptors on the liver for CM and their remnants to deposit TAGs.

Question 16

Where are ApoE apolipoproteins found and what is their function?

Answer 16

ApoE is the major protein for remnant lipoproteins. This binds to LRP and LDL receptors, so CMR can deposit TAGs in liver and IDL deposits

Question 17

What is the function of CETP enzyme in regards to HDL?

Answer 17

CETP converts HDL3 into HDL2 (mature)

Question 18

What familial disease is associated with a deficiency in Lipoprotein lipase or ApoC-II? What are some features about this condition?

Answer 18

Familial Hyperchylomicronemia (Type 1 Hyperlipidemia) is associated with HELLA HIGH triglycerides >1000 mg/dL. Severe Hypertriglyceridemia presents with cloudy plasma.

Question 19

List at least 3 clinical manifestations linked with Primary (Type I) Hypertriglyceridemia.

Answer 19

1. Recurrent Pancreatitis
2. Eruptive xanthomas
3. Lipemic (milky) plasma
   * Associated with high levels of chylomicrons*

Question 20

What familial disease is linked with high total cholesterol but normal TAGs? What defects could result in this condition?

Answer 20

Familial Hypercholesterolemia (FH, Type IIa Hyperlipidemia) is associated with HIGH cholesterol and LDL levels, but normal TAGs. This is linked to defects in function of LDL receptors or high Apo B100 to LDL interaction (Hyperbetalipoproteinemia). 
*IIa is complete loss of LDLR, but IIb is linked to partial loss*

Question 21

List at least 2 clinical manifestations linked to Primary (Type IIa) Hypercholesterolemia.

Answer 21

1. *Tendon Xanthomas on hands and feet

2. Corneal Arcus

Question 22

What familial disease is associated with a deficiency in ApoE and elevated IDL?

Answer 22

Familial Dysbetalipoproteinemia (Type III Hyperlipidemia) is assocaited with an accumulation of CMR and IDL. This results in elevated TAGs and total choelsterol levels.

Question 23

The ____ allele is the least common and associated with Type ___ Hyperlipidemia. This will present as elevated TAGs and total cholesterol.

Answer 23

The ApoE2 allele is least common and linked with Type III Hyperlipidemia (Dysbetalipoproteinemia).

Question 24

List at least 2 clinical manifestations linked to Type III Hyperlipidemia.

Answer 24

1. *Palmar Crease Xanthomas

2. Tuberous Xanthomas in the limb joints such as the elbows and knees.

Question 25

A deficiency in what apolipoprotein will result in “corneal clouding” and a common disorder of HDL? What are the expected lab values?

Answer 25

Apo A-1 Deficiency (Hypoalphalipoproteinemia, FHA) is linked to corneal clouding, low HDL count (<10 mg/dL) and an excess of non-esterified cholesterol.

Question 26

A deficiency in what enzyme would result in “fish eye” disease? What are the expected lab values?

Answer 26

LCAT deficiency would result in increased levels of free cholesterol and low HDL (<10 mg/dL). This results in more severe corneal opacifications than cases of Apo A-1 deficiency.

Question 27

A deficiency in ABCA1 would result in what disease? Briefly describe the pathogenesis and associated symptoms.

Answer 27

Tangier-Disease involves impaired ABCA1 in peripheral tissues prevents HDL maturation and leads to a backup of cholesterol in peripheral tissue and liver macrophages. This presents as yellow discoloration to tonsils (cholesterol accumulation).

Question 28

Why would medium chain fatty acids be given to someone with severely high TAGs?

Answer 28

Medium chain FAs go directly into blood of the portal system and can be metabolized by the liver. This bypasses the exogenous transport through chylomicrons associated with Type I Dyslipidemia.

Question 29

What 2 things can be deficient in someone with Type I Dyslipidemia?

Answer 29

Apo C-II or LPL can be deficient in someone with Familial Hyperchylomicronemia.

Question 30

A deficiency in ApoE can result in elevated levels of _____. Why?

Answer 30

Elevated IDL levels can be associated with a lack of ApoE because this is a major protein of remnant lipoproteins.

Question 31

What drug increases LPL activity, increases HDL and decreases FFA release?

Answer 31

Niacin (Vitamin B3) is highly effective as increasing HDL-C.

Question 32

What drugs are best used to treat patients with hypertriglyceridemia? How do they do this?

Answer 32

Fibrates target transcription factor PPAR alpha to stimulate lipid metabolism. Gemfibrozil is an example.