4.4 Lipid Disorders

Question 1

What is dyslipidaemia? What’s the difference between 1° and 2° dyslipidaemia?

Answer 1

• Dyslipidaemia = abnormal levels of lipid in the blood, typically high LDL, low HDL, or high TAG
• 1° is genetically inherited, whereas 2° involves some kind of other medical condition or lifestyle factor

Question 2

When cholesterol is carried in the core of lipoproteins, what form is it in?

Answer 2

Cholesterol esters.

Question 3

What distinguishes HDL particles from all other lipoproteins in terms of their apolipoproteins? What about Lp (a)/”little A”

Answer 3

HDLs have no Apo-B48 or Apo-B100. (This is why they’re good cholesterol)

Lp (a) has apo (a) — this makes it stickier than regular LDL; worse.

Question 4

What are the functions of apolipoproteins?

Answer 4

• Structural role
• Lipoprotein formation
• Activate/inhibit metabolic enyzmes
• Act as ligands for receptor cells (Lipoprotein Lipase, for example)

Question 5

Why are hepatic LDL receptors so important?

Answer 5

Because they are crucial for reuptake of LDL from the bloodstream. If this weren’t the case, the particles would stay in the blood, causing increased cardiovascular risk.

Question 6

What are Lp (a) particles fundamentally? What is their effect on cardiovascular risk?

Answer 6

• They are LDL particles with an additional Apo (b) apolipoprotein (also have Apo-B100) in 1:1 ratio.
• Associated with increased cardiovascular risk.

Question 7

What is the main type of primary dyslipidaemia? What are the three main types of mutation that can cause it?

Answer 7

• Main type is familial hyperlipidaemia (FH)
• Three main mutations are in Apo-B, LDL receptors, and PCSK9

Question 8

What is the function of PSCK9 protein? Why might we inhibit it?

Answer 8

• Function is to promote degradation of LDL receptors in liver
• By inhibiting, we have more receptors, and hence more LDL uptake

Question 9

Can Familial Hypercholesterolaemia mutations be homozgyous or heterozygous (or both)? How does this affect life expectancy?

Answer 9

• Can be both
• In homozogyous mutations, extreme rates of CVD, can die as early as 10, and unlikely to live past 30 years of age.

Question 10

Outline the approach to management of dyslipidaemia, including 1st, 2nd, and 3rd line treatment

Answer 10

• Lifestyle and diet (reduce alcohol, weight loss, quit smoking, exercise)
• Medications (statin 1st line, ezetimide [inhibits absorption] and PCSK9 inhibitors 2nd line, apheresis, mRNA inhibition of apoB and liver transplant 3rd line)

Question 11

Outline the mech of SGLT2 inhibitors to reduce glucose (and therefore CV risk)

Answer 11

Prevent resorption of glucose in the kidneys. Promote excretion. (SGLT2 = sodium-glucose transporters).

Question 12

Why does insulin resistance increase the amount of lipid circulating in the blood. What does this predispose to, importantly?

Answer 12

• Insulin impairs lipolysis in adipose tissue
• Once adipose is resistant to insulin, this leads to more lipolysis, and thus higher circulating lipids
• This predisposes to ectopic lipid deposition in skeletal muscle, the pancreas, and the liver.

Question 13

Describe how ectopic lipid deposition can occur in the pancreas, skeletal muscle, and liver in the setting of insulin resistance. After all, these organs can usually take up fatty acids…

Answer 13

• In insulin resistance, we have suppressed impairment of lipolysis, leading to higher circulating lipid levels
• This leads to deposition of lipids in these tissues at rates higher than they can metabolise or otherwise output.
• Over time, leads to visceral fat accumulation

Question 14

What are two consequences of ectopic lipid deposition on skeletal muscle?

Answer 14

• Oxidative stress
• Mitochondrial dysfunction

Question 15

What are some consequences of ectopic lipid deposition on the liver?

Answer 15

• Fibrosis
• Inflammation
• Ox stress

Question 16

What happens to adipose tissue in the setting of insulin resistance?

Answer 16

• Macrophage infiltration
• Leads to inflammation and fibrosis

Question 17

At a basic biochemical level, explain how insulin works, and thus how insulin resistance occurs

Answer 17

• Insulin triggers moving of GLUT-4 containing vesicles to cell surface, allowing glucose in the cell
• In insulin resistance, this process is impaired

Question 18

How can insulin resistance in the liver worsen itself via a positive feedback loop

Answer 18

• Insulin usually inhibits TAG accumulation in the liver
• When insulin resistance occurs, TAGs accumulate, further impairin insulin signalling pathways

Question 19

Does insulin resistance increase or decrease hepatic VLDL output? What about oxidative stress

Answer 19

Increases both.

Question 20

Obstructive sleep apnoea can trigger insulin resistance by intermittent activation of…

Answer 20

The sympathetic nervous system (during apnoeas)

Question 21

How does obesity cause insulin resistance? How does insulin resistance cause obesity?

Answer 21

1. Visceral fat deposition causes low-grade inflammation, disrupting insulin signalling. Ectopic lipids in skeletal muscle, adipose, and liver can all impair secretion/recognition of insulin.
2. As levels of insulin increase in response to decreased sensitivity, the body is prompted to produce and store more adipose tissue, thus potentially leading to obesity.

Question 22

Give two examples of diseases that can cause sleep apnoea

Answer 22

1. Thyroid disease
2. Sleep apnoea