***Lipid metabolism and atherosclerosis

Question 1

List the modifiable and non-modifiable risk factors for coronary heart disease

Answer 1

Modifiable
• Hyperlipidemia (LDLS bad, HDL good. Exercise increases HDL)
• Hypertension
• Smoking

Non- modifiable
• Age (increases with age)
• Sex (males higher)
• Genetics (family history of diabetes etc)

Question 2

List how diabetes and the amino acid homocysteine cause hyperlipidemia

Answer 2

Diabetes
· Blood sugar levels affects the level of non- enzymatic glycosylation of proteins, particularly collagen in vessel walls
· Glycosylation within vessel walls trap proteins including LDLs, promoting atherosclerosis

Hyperhomocystinemia:
· Homocysteine is produced when proteins are broken down
· A high homocysteine level, also called hyperhomocysteinemia, can contribute to arterial damage and blood clotsin blood vessels
· High homocysteine levels usually indicate a deficiency in vit b-12

Question 3

What is cholesterol?

Answer 3

· Cholesterol is a fat-like substance in the body
· Essential for maintenance of cell membranes, regulating membrane fluidity and permeability
· Also makes essential:
PG2 (endothelial function) and Thromboxane (platelet aggregation to stop bleeding). Leukotriene (inflammatory factor)

Question 4

How is cholesterol transported in the blood?

Answer 4

· Cholesterol is carried in the blood by lipoproteins because it insoluble in blood. The main types of lipoproteins are high-density lipoprotein (HDL) and low-density lipoprotein (LDL)

Question 5

What are two ways cholesterol is metabolised?

Answer 5

• Endogenous

* Exogenous

Question 6

Describe the endogenous pathway of cholesterol metabolism

Answer 6

· Cholesterol can be made from the mevalonate pathway
· Krebs cycle: glucose turns into a pyruvate (3 carbon molecule) which is broken down to form acetyl coA (2 carbon molecule)
· Two acetyl coA join to start off the mevalonate pathway
· Acetyl coA enters a reaction with HMG- CoA reductase to form cholesterol
· This cholesterol is combined with triglycerides and packed into apolipoprotein B-100 (LDL) which turns into VLDL. Then, HDL donates Apo CII and ApoE to turn VLDL into LDL and the rest of that cycle is history

Question 7

Describe the exogenous pathway of cholesterol metabolism

Answer 7

· Dietary cholesterol is packed into a chylomicron vesicle
· From here, the chylomicron travels to the liver, where it is combined with endogenous cholesterol and triglycerides, which is then packed into very low density lipoproteins (VLDL)
· Tissues extract triglycerides from VLDL, turning it into LDL
· Cells take up LDL via endocytosis· Excess cholesterol is exocytosed and delivered to HDL which returns it to the liver in a process called reverse cholesterol transport
· The liver turns the cholesterol into bile which is sent to the intestine where some of it is excreted into faeces and some of it absorbed back and transported into the liver

Question 8

What is reverse cholesterol transport?

Answer 8

· HDL ApoAi protien bond to Macrophages through ABC1 receptor to collect cholesterol from the tissue
· Transport back to the liver to recycle

Question 9

How can NO can trigger atherosclerosis?

Answer 9

A deficiency in NO production leads to:
· excess constriction of blood vessels
· platelet activation = blood clotting,
· increases vessels permeability thus allowing bad lipoproteinsand various toxins in

· Endothelial dysfunction: when LDLs are high, they can go through the endothelium and deposit in the tunica intima

Question 10

Describe the pathogenesis of atherosclerosis

Answer 10

· A deficiency in NO production leads to excess constriction of blood vessels, activates of platelets = blood clotting, increases the stimulation of inflammation in blood vessel walls, and increases vessels permeability thus allowing bad lipoproteinsand various toxins in
· Endothelial dysfunction: when LDLs are high, they can go through the endothelium and deposit in the tunica intima
· These LDLs are oxidised. Oxidised LDLs activates endothelial cells which causes them to express receptors that attract WBCs
· WBC’s (monocytes and T cells) can move into tunica intima via diapedesis
· Monocytes mature into macrophages which phagocytose the LDLs. They then become foam cells
· Foam cells cause the migration and proliferation of smooth muscle cells from tunica media into tunica intima. This increases the synthesis of collagen. This contributes to hardening of the atherosclerotic plaque
· Meanwhile, foam cells die releasing their lipid content. This causes the plaque to grow. As it grows, it can eventually cause rupturing of the endothelium
· To fix the rupture, thrombosis occurs. This forms a huge clot that can impeded blood flow