Lecture 54

Question 1

cholesterol as risk factor for CHD

Answer 1

• been studying history of cholesterol and CHD risks since about 1900
• first, focus was on cholesterol
• then, focus was on LDL

pg 1405

Question 2

blood lipids as risk factor for CHD

Answer 2

Framingham Heart Study

• initiated in 1948 under the direction of the National Heart, Lung, and Blood Institute (under the NIH)
• committed to identify the common factors that contribute to CVD
• first epidemiological studies to demonstrate an inverse relationship between HDL-cholesterol and increased CHD
• high LDL and low HDL are both risk factors for CHD

pg 1406

Question 3

cellular LDL uptake and clearance

Answer 3

1. Apo B-100 remaining in LDL as a ligand recognized by the LDL receptors (LDLR) on the surface of the cells
2. once LDL is recognized by LDLR, the particle enters the cell via receptor-mediated clathrin-dependent endocytosis
3. vesicle is moved through the endocytic pathway as the LDLR uncouples from the ligand and can be recycled back to the membrane whereas the LDL fuses with the lysosomes
4. in the lysosomes, acid hydrolyses break down lipids -> apo B-100 and respective monomers are recycled

pg 1407

Question 4

hypercholesterolemia

Answer 4

• condition characterized by very high levels of cholesterol in the blood (200-400 mg/dL) and an early atherosclerosis/CVD
• xanthomas (lipid deposits in skin) are commonly seen

pg 1408

Question 5

familial hypercholesterolemia (FH)

Answer 5

• loss of function mutation in the LDL receptor
• autosomal dominant
• incomplete dominance
• homozygous or compound heterozygous: have extremely high levels of LDL-C and death usually in their 20s (cholesterol higher than 400)
• heterozygous: onset of disease is later in life and less severe with mid-high range of LDL-C

pg 1409

Question 6

familial defective apoB-100 (FDB)

Answer 6

• loss of function defect in the apo B-100 protein affecting binding to LDLR
• autosomal dominant
• only small portion of apo B-100 is responsible for binding
• R3500Q is the most studied mutation

pg 1410

Question 7

regulation of LDLR levels

Answer 7

oversupply of cholesterol will:

1. inhibit de novo synthesis of cholesterol through SREBP-2 mediated downregulation of HMG CoA-reductase expression
2. inhibit expression of LDLR via the same SREBP-2 dependent transcriptional mechanism resulting in decreased LDL uptake
3. activate ACAT to produce more cholesterol esters and store them within intracellular lipid droplets

pg 1411

Question 8

regulation of LDLR levels by statins

Answer 8

1. statins inhibit HMG CoA reductase, leading to a decreased concentration of cholesterol within the cell
2. low intracellular cholesterol stimulates the synthesis of LDL receptors
3. increased number of LDL receptors promotes uptake of LDL from blood
4. low intracellular cholesterol decreases the secretion of VLDL

pg 1412

Question 9

hypercholesterolemia pt 2

Answer 9

• gain of function defect in the PCSK9 protein leading to enhanced degradation of LDLR
• autosomal dominant
• more than 30 different gain of function mutations have been identified

pg 1413

Question 10

PCSK9 function in LDLR turnover

Answer 10

• PCSK9 is produced mainly in the hepatocytes, secreted in the plasma where it binds the LDLR
• under transcriptional regulation of SREBP-2
• PCSK9 binding does not interfere with the LDLR’s ability to recognize LDL particles
• incapacitates the LDLR’s ability to return to the surface of the hepatocyte and bind to a new LDL molecule
• LDLR are destroyed, their concentration at the surface is reduced, and leads to reduction of LDL clearance from the plasma

pg 1414

Question 11

PCSK9 inhibitors

Answer 11

• drugs
• two PCSK9 inhibitors (alirocumab and evolocumab)
• fully humanized monoclonal antibodies
• available as subq injections
• when combined with statin therapies, PCSK9 inhibitors provide potent LDL-C lowering

pg 1415

Question 12

mechanisms of atherosclerosis

Answer 12

1. in response to endothelial injury, monocytes adhere to endothelial cells, move to the subendothelium, and are converted into macrophages
2. macrophages consume excess modified lipoprotein, becoming foam cells
3. foam cells accumulate, releasing GFs and cytokines that stimulate migration of SMCs from media to intima; there, the SMC proliferate, produce collagen, and take up lipids -> potentially becoming foam cells
4. low-affinity, nonspecific, and nonregulated scavenger receptors take up modified LDL
5. high-affinity receptors specific for LDL are downregulated when the cell has sufficient cholesterol

pg 1416

Question 13

inhibitors and activators of LDL oxidation (modification)

Answer 13

activators: superoxide, nitric oxide, hydrogen peroxide, other oxidants (commonly from inhaled smoke)
inhibitors: vitamin E, ascorbic acid (vitamin C), β-carotene, other antioxidants from the diet
want to inhibit LDL oxidation to prevent atherosclerosis

Question 14

atherosclerosis and environment

Answer 14

smoking leads to endothelial cell dysfunction and injury, prothombotic state, and plaque vulnerability

pg 1417