Atherosclerosis 1

Question 1

What is the progression process of Atherosclerosis?

Answer 1

1. Atherosclerosis may start when certain factors damage the inner layers of the arteries (i.e. tunica intima)
2. Plaque may begin to build up where the arteries are damaged. Over time, plaque hardens and narrows the arteries
3. Eventually, an area of plaque can rupture. When this happens, platelets accumulates at the site of the injury and clump together to form blood clots. Clots narrow the arteries even more, limiting the flow of oxygen-rich blood to the body
4. Depending on which arteries are affected, blood clots can worsen angina (chest pain) or cause a heart attack or stroke

Question 2

What can Atherosclerosis damage and how ?

Answer 2

• Coronary arteries = supply oxygenated blood to the heart. Atherosclerosis in them can cause “ischemic heart disease”. A common symptom is angina, which is chest
  pain or discomfort. This may result in a heart attack
• Carotid arteries = supply oxygenated blood to the brain. Narrowing of these arteries
  by plaque leads to “carotid artery disease” and this may result in a stroke
• Peripheral arteries = supply oxygenated blood to the arms, legs, and pelvis. If these major arteries are narrowed or blocked, we may experience numbness, pain, and, sometimes, dangerous infections in the limbs
• Renal arteries = supply oxygenated blood to the kidneys. Atherosclerosis in these arteries lead to chronic kidney disease

Question 3

Two Major Factors for Atherosclerosis ?

Answer 3

1. Unhealthy blood cholesterol levels: This includes high LDL and low HDL cholesterol
2. High blood pressure: Blood pressure is considered high if it stays at ot above 140/90 mmHg over time
   - Smoking: can damage and tighten blood vessels, raise cholesterol levels, and raise
   blood pressure. Smoking also doesn’t allow enough oxygen to reach the body’s tissues.
   - Overweight or obesity
   - Lack of physical activity: A lack of physical activity can worsen other risk factors for
   atherosclerosis, such as unhealthy blood cholesterol levels, high blood pressure, diabetes, and being overweight or obese
   - Old age : As we get older, the risk for atherosclerosis increases. Genetic or lifestyle factors cause plaque to build up in your arteries as you age

Question 4

What are some pharmaceutical interventions for high cholestrol levels ?

Answer 4

1. Statin:
   Lovastatin found in 1978 is a fungal metabolite isolated from cultures of
   Aspergillus terreus. A potent competitive inhibitor of HMG-CoA reductase (Ki=1 nM)
2. Bile acid-binding resins (anion-exchange):
   Bind negatively charged bile salt in the intestine
3. Fibrates:
   Regulates lipoprotein metabolism
4. Nicotinic acid (and derivatives):
   A B vitamin that inhibits hepatic diacylglycerol
   acyltransferase-2, a key enzyme for triglyceride synthesis
5. Specific cholesterol absorption inhibitors: Ezetimibe acts at the brush border of the small
   intestinal mucosa to specifically inhibit the NPC1L1 transporter and reduces cholesterol absorption by about 50 %
6. Omega-3 fatty acids:
   They are long-chain polyunsaturated acids such as α–linolenic acid and eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), that have potential cardioprotective effects

Question 5

What are animal ‘fats’ found in butter, lard etc. mixed with?

Answer 5

It is mostly saturated (40%-

60%) mixed with monounsaturated (30%-50%), only traces of polyunsaturated fats

Question 6

Explain the percentage of saturated and unsaturated in Plant ‘fats’ ?

Answer 6

Plant ‘fats’ 10%-20% saturated, 80%-90% unsaturated. Exact
composition varies e.g. Olive oil 79% oleic acid (monounsaturated), sunflower seed oil 75% linoleic acid (polyunsaturated)

Question 7

What food is high in polyunsaturated fat ?

Answer 7

• Vegetable oils

- Some nuts (e.g. walnuts)

Question 8

What food is high in monosaturated fat ?

Answer 8

• Olives

- Olive oil

Question 9

What fatty acid is Linoleic acid?

Answer 9

Linoleic acid is an omega-6-fatty acid

Question 10

What fatty acid is α-Linoleic acid?

Answer 10

α-Linoleic acid is an omega-3-fatty acid

Question 11

Digestion and Absorption of Fats ?

Answer 11

1. Bile salts from liver coat fat
   droplets
2. Pancreatic lipase and colipase break down fats into monoglycerides and fatty acids stored in micelles
3. Monoglycerides and fatty acids move out of micelles and enter cells by diffusion
4. Cholesterol is transported
   into cells
5. Absorbed fats combine
   with cholesterol and proteins in the intestinal cells to form chylomicrons
6. Chylomicrons are removed by the lymphatic system

Question 12

What do capillary endothelial cells in target tissues (muscle and adipose) have ?

Answer 12

They have Lipoprotein Lipase attached on the lumen side

Question 13

What do Lipoprotein Lipase cleave off ?

Answer 13

Fatty acids which enter cells

Question 14

What is it called when the chylomicron has offloaded most of the TAG ?

Answer 14

It is called a remnant and is removed from circulation by the liver

Question 15

What does transport from gut to tissues use ?

Answer 15

Chylomicrons

Question 16

Give some background information about Chylomicrons ?

Answer 16

• Stable and water soluble particles
• mixture of lipid and apolipoproteins
• have phospholipid and cholesterol on outer layer
• triglycerides, cholesterol and fat-soluble vitamins in the inner core
• chylomicrons are released into the lymph system and then into the blood

Question 17

What are the different classes of lipoproteins ?

Answer 17

• VLDL – Very Low Density Lipoprotein
• IDL – Intermediate Density Lipoprotein
• LDL – Low Density Lipoprotein
• HDL– High Density Lipoprotein

Question 18

What are the different types of lipid in Chylomicrons ?

Answer 18

1. Neutral fats (tri, di and monoacylglycerols)
2. Phospholipids
3. Steroids (cholesteryl esters etc.)
4. Vitamins (fat-soluble)

Question 19

Explain Neutral Fats (aka Triglycerides) ?

Answer 19

• Non polar, water insoluble
• Differ according to identify and placement of their 3 fatty acids
• Simple triglycerides contain one type of fatty acid
• Mixed triglycerides contain 2 or 3 types

Question 20

Explain Phospholipids ?

Answer 20

• Amphipathic molecules – contain both hydrophobic and hydrophilic components
• When hydrated form extended bilayers, both lamellar and closed vesicular structures (liposomes)
• Similar to triglycerides but contain a phosphate group instead of one of the fatty
  acids
• Important component of cell membranes

Question 21

Explain Cholesterol ?

Answer 21

• Cholesterol is made primarily in the liver cell

- ~80 % synthesised in the liver and 20 % ingested and absorbed from food

Question 22

Use of Cholesterol in the membrane ?

Answer 22

• Important in controlling membrane fluidity
• Binds to hydrophobic tails of the phospholipids
• Important in packing the phospholipids more closely together
• The more cholesterol, the less permeable the membrane
• Important in keeping membrane stable at 37 °C

Question 23

What are the fat soluble vitamins ?

Answer 23

They are vitamins A, D, E and K

Question 24

What is the function of Chylomicrons ?

Answer 24

Transport TAGs from intestine to peripheral tissues

• main apoprotein is apoB48 (intestine)
• also contain apoproteins A, C and E
• after hydrolysis by lipoprotein lipase (LPL) remnants taken up by the liver

Question 25

What is the function of VLDLs?

Answer 25

Transport TAGs from liver to peripheral tissues

• main apoprotein is apoB100
• also contain apoC and apoE

Question 26

What is the function of HDLs?

Answer 26

Transport cholestrol from peripheral tissues back to liver

• main apoproteins are apoAI and apoAII
• participates in metabolism of other particles

Question 27

What happens under conditions of prolonged fasting/starvation or diabetes?

Answer 27

• Oxaloacetate is consumed to form glucose
• This reduces the availability of oxaloacetate in the TCA cycle resulting in accumulation of acetyl CoA
• When acetyl CoA builds up in the liver beyond the capacity of the TCA cycle to
  consume it, ketone bodies are made
• These are released into the blood and used as fuel by other cells especially in the
  cardiac muscle cell
• Excess acetyl CoA may undergo FA anabolism i.e. more FA and triglyceride (TG)
• Excess acetyl CoA may be directed more towards cholesterol biosynthesis