W2 Lipid Homeostasis and Antihyperlipidemic drugs

Question 1

What are lipids?

Answer 1

Lipids like free fatty acids, cholesterol (& its esters) and triglycerides are body fats that are either synthesized within cells (endogenous lipids) or derived from dietary fat (exogenous lipids)

Question 2

What is cholesterol?

Answer 2

An essential component that makes the
cell membrane and modulates membrane fluidity, and critical for cell growth and viability; Precursor for steroid hormones, vitamin D and bile salt

Question 3

What are triglycerides?

Answer 3

largely through diet, but synthesised in
the liver as well. supply energy/fuel to muscle and other tissues

Question 4

Cholesterol level in the blood

Answer 4

Dietary:

• Bile emulsifies dietary lipids (including cholesterol) and facilitates its absorption. Following this, bile salts are recycled via the hepatic portal vein (entero-hepatic circulation)
• In the intestine, cholesterol from the diet enters the micellar membrane, as do fatty acids and monoglycerides derived from dietary triglycerides.

Intestinal cholesterol is absorbed and transported to the liver, where it is mixed with hepatic cholesterol.
* Some portion of the cholesterol is immediately pumped out of the body (into the intestinal lumen) by the heterodimeric ATP-binding cassette transporter protein complex of ABCG5/G8.
* Cholesterol is absorbed from micelles into the intestinal wall through a recently identified protein channel, Niemann-Pick C1 Like 1 protein (NPC1L1) on the enterocyte plasma membrane.

Question 5

What is de novo cholesterol synthesis in the liver?

Answer 5

De novo- the synthesis of complex molecules from simple molecules such as sugars or amino acids (e.g. gluconeogenesis)

Up to 70-80% of the cholesterol in humans is synthesised de novo by the liver, and 10% is synthesised de novo by the
small intestine.

HMG-CoA reductase (HMGR), a highly conserved, membrane-bound enzyme,
catalyses a rate-limiting step in sterol and isoprenoid biosynthesis and is the primary target of hypocholesterolemic drug
therapy

Question 6

Lipid homeostasis:

Question 7

What are the functions of Apolipoproteins?

Answer 7

1) Serving a structural role,
2) Acting as ligands for lipoprotein
receptors,
3) Guiding the formation of lipoproteins,
4) Serving as activators or inhibitors of
enzymes involved in the metabolism of
lipoproteins

Question 8

What are the types of lipoproteins? (4)

Answer 8

Chylomicrons
Chylomicron Remnants
Very Low-Density Lipoproteins (VLDL)
Intermediate-Density Lipoproteins (IDL)

Question 9

What are VLDL?
What are IDL?

Answer 9

Very low-density lipoproteins
- They are produced by the liver and are triglyceride-rich

Intermediate-Density Lipoproteins
- The removal of triglycerides from VLDL by muscle and adipose tissue results in the formation of IDL particles which are enriched in cholesterol

Question 11

What are chylomicrons?
What are chylomicron remnants?

Answer 11

Chylomicrons are large triglyceride-rich particles made by the intestine, which are involved in the transport of dietary triglycerides and cholesterol to peripheral tissues and the liver.

The removal of triglyceride from chylomicrons by peripheral tissues results in smaller particles called chylomicron remnants

Question 12

What is a pro-drug?

Answer 12

A drug that is inactive and has to be converted into its active state by Cytochrome P450 enzyme (CP450)

Question 13

What are LDL?

Answer 13

Low-Density Lipoproteins
- Derived from VLDL and IDL particles
- Enriched in cholesterol
- LDL carries the majority of the cholesterol that is in circulation
- Each LDL particle contains one Apo B-100 molecule.
- High levels of Apo B-100 are associated with an increased risk of atherosclerosis

Question 14

What are HDL?

Answer 14

• High density lipoproteins
• These particles contain cholesterol and phospholipids
• Apo A-I is the core structural protein and each HDL particle may contain multiple Apo A-I molecules
• High levels of Apo A-I is associated with a
  DECREASED risk of atherosclerosis.

Question 15

What are the functions of HDL particles?

Answer 15

HDL particles play an important role in reverse cholesterol transport from peripheral tissues to the liver, which is one potential mechanism by which HDL may be anti-atherogenic

1. Antiapoptotic
2. Decreases expression of adhesion molecules (anti-inflammatory)
3. Decreases LDL oxidation (antioxidative)
4. Ameliorates endothelial function
5. Stimulates macrophage cholesterol reflux

Question 16

What are the steps in the exogenous pathway of lipid homeostasis? (3)

Answer 16

1. The exogenous lipoprotein pathway starts with the incorporation of dietary lipids into chylomicrons in the intestine.
2. In the circulation, the triglycerides (TG)
   carried in chylomicrons are metabolized in
   the muscle and adipose tissue by lipoprotein lipase (LPL) releasing free fatty
   acids (FA), which are subsequently
   metabolized by muscle and adipose tissue,
   and chylomicron remnants are formed.
3. Chylomicron remnants are then taken up by the liver.

Question 17

What are the steps in the endogenous pathway of lipid homeostasis? (3)

Answer 17

1. The endogenous lipoprotein pathway begins in the liver with the formation of VLDL
2. The triglycerides carried in VLDL are metabolized in the muscle and adipose tissue by lipoprotein lipase releasing free fatty acids and IDL are formed.
3. The IDL are further metabolized to LDL, which are taken up by the LDL receptor in numerous tissues including the liver, the
   predominant site of uptake.

Question 18

What is reverse cholesterol transport?
How does Reverse cholesterol transport occur?

Question 19

Pathophysiology of atherosclerosis:

What is responsible for atherosclerosis?

Process of atherosclerosis occurance:

Answer 19

• LDL (oxidised)
• Start recruiting Platelets
• Causes fatty streak, which causes endothelial cell injury/dysfunction
• This recruits macrophages in artery wall to form atheroma, following an atherosclerotic lesion

1) endothelial dysfunction
2) formation of lipid layer or fatty streak within the intima
3) migration of leukocytes and smooth muscle cells into the vessel wall
4) foam cell formation
5) degradation of extracellular matrix

Cholesterol and triglycerides have the potential to build up in the arteries, clogging and narrowing the blood vessels.
This build-up in the arteries can raise blood pressure (arterial resistance) and the risk of blood clots (thrombosis and
embolism), increasing the chances of heart attack or stroke

Question 20

Familial hyperlipidemia

Answer 20

Hyperlipidemia:
Abnormally high levels of fats (lipids) in the blood, which include cholesterol and triglycerides.

Familial (Genetic)
Familial combined hyperlipidaemia is the genetic cause that leads to a high level of both LDL cholesterol and triglycerides which develops at a young age and
increases the risk of early coronary heart disease.
Familial hypercholesterolemia and polygenic hypercholesterolemia are denoted by the high cholesterol content.

Familial hyperapobetalipoproteinemia is a condition with high levels of apolipoprotein B, which is part of LDL cholesterol.

Secondary: Obesity, smoking, high fat diet, alcohol and others

Question 21

What are the pharmacological options of lipid-lowering?

Answer 21

1. Cholesterol synthesis inhibition
2. Intestinal absorption
3. Lipoprotein lipase activity
4. HDL

Question 22

Cholesterol synthesis inhibition

Answer 22

Statins competitively inhibit the HMG-CoA
reductase, leading to reduced cholesterol.
To compensate for the cholesterol level, the liver recruits more LDL from the circulation (LDL clearance from the blood)

Generally well tolerated but may cause some adverse effects:
GI disturbances, skeletal muscle myopathy
(dose-dependent effects but higher in
hypothyroidism and high alcohol intake),
Myalgia (muscle ache), myositis with
rhabdomyolysis

CYP inhibitors (grapefruit juice, diltiazem,
amlodipine and macrolide antibiotics) worsen statin’s adverse effects
Contraindicated in pregnancy (risk of congenital abnormalities)

• Atorvastatin (Longer half-life, taken at
  any time)
  *Pravastatin (short half life, taken at
  night)
  *Rosuvastatin (longer half-life, taken at
  statins’
  Statins competitively inhibit the HMG-CoA
  reductase, leading to reduced cholesterol.
  To compensate for the cholesterol level, the liver recruits more LDL from the circulation (LDL clearance from the blood)

Question 23

Cholesterol absorption inhibition

Answer 23

Anion exchange resins:
(cholestyramine and colestipol) binds with bile salts (insoluble complex) and excreted in faeces

Outcome: reduced intestinal cholesterol absorption, cholesterol directed to compensate for bile
loss, LDL cholesterol clearance.

Unpalatable, digestive problems, interfere with fat-soluble nutrients and drugs
Limited use (but still handy if all other drugs to reduce LDL isn’t an option, e.g pregnancy)

Ezetimibe: Block the transport protein Niemann-Pick C1 Like 1 (NCP1L1) in the gut wall (highly
potent)

Outcome: reduces intestinal cholesterol absorption, without affecting bile
Digestive problems, myalgia, fatigue and headache (not recommended as the first line drug for IHD)
Contraindicated in pregnancy

Question 24

Lipoprotein lipase activity

Answer 24

Fibrates elicit complex effects on circulating effects (not completely understood)
First line in hypertriglyceridaemia (but not ideal for LDL reduction)
Fibrates activate a class of nuclear (steroid)
receptors/transcription factor, PPARa, to upregulate the expression of lipoprotein lipase and increase the lipoprotein lipase-mediated lipolysis.
* Decrease TG level
* Increase HDL synthesis, RCT, LDL size
Anti-inflammatory, Anti-thrombotic, fibrinolytic
Myositis, muscle aches and breakdown
A combination of fibrates with statin worsens myalgia
*Clofibrate,
*Fenofibrate,
*Gemfibrozil

Question 25

Increasing HDL level in the circulation:
What can be taken?
What are its SE?

Answer 25

Nicotinic acid receptor agonist: Niacin (essential vitamin B3)

High doses (>1.5<3g daily) – reduce the circulation of VLDL and LDL and increase circulating HDL (MoA unclear)

*Severe skin flushing combined with dizziness
(>30-40% discontinue medication).
*Tachycardia.
*Itching.
*Nausea and vomiting.
*Abdominal pain.
*Diarrhoea.
*Gout.
*Liver damage.

Question 26

Coronary Circulation

Answer 26

• Two tiny arteries leaving out the aorta
• Profuse blood to the myocardium
• Handles high pressure (irrespective of heart contraction or relaxation)
• Thickening of the internal surface of arteries or progression of atherosclerotic lesions, occlude and affect
  oxygen supply to heart muscles (ISCHEMIA)- a major
  cardiac problem- progress to angina, coronary artery disease.
• Coronary thrombosis- Myocardial Infarction (MI)