Cholesterol and lipoproteins

Question 1

Content of lipoproteins

Answer 1

Apolipoproteins, cholesterol ester, cholesterol, triglyceride

Question 2

Ligands for LDL receptors

Answer 2

Apolipoproteins ApoA100, ApoB48

Question 3

Activators of lipase

Answer 3

Apolipoproteins ApoC3, ApoA2

Question 4

Transport of cholesterol into enterocytes

Answer 4

Thanks to the transporter NPC1L1, that can be targeted by the drug Ezetimide.

Question 5

Assembly of lipoproteins is facilitated by

Answer 5

ApoB48 and MTTP

Question 6

Simplified depiction of cholesterol synthesis:

Answer 6

Acetyl-CoA → acetoacetyl-CoA → HMG-CoA → mevalonate → squalene → cholesterol

Question 7

PCKS9

Answer 7

Protease secreted by the liver that attaches to the LDL receptor on the surface of Hepatocytes. PCSK9 increases receptor turnover by inducing the internalization and intracellular degradation of the LDL receptor.
-> decreases the total number of LDL receptors available and essentially has the same effect as a LOF mutation in the LDL receptor itself.

People with mutations in the PCSK9 gene have a lower cardiovascular risk than the general population.

Question 8

Guidelines for target cholesterol levels

Answer 8

Lower is the better.

• Target of < 150 mg/dL if no high-risk factors
• Target of <100 mg/dL if high-risk factors

Patients with atherosclerotic plaques: LDL levels between 30-50 mg/dL for effectively reducing the number of CV events.

Question 9

Statins mechanism of action

Answer 9

Competitively inhibit HMG-CoA reductase to inhibit endogenous synthesis of cholesterol in the liver

Question 10

Newer statins and their indication

Answer 10

Atorvastatin and Rosuvastatin
High dose 40-80 mg
Given when cholesterol levels must be lower of 50% or more

Question 11

Older statins ad their indication

Answer 11

Pravastatin, Simvastatin, Lovastatin, Fluvastatin, Pitavastatin.
Used less, when the need is lowering of a moderate amount.

Question 12

Statins side effects

Answer 12

Very safe drugs.
They can cause statin-induces myopathy -> creatine kinase levels must be checked after 2 weeks from the beginning of the therapy.

Question 13

Niacin

Answer 13

No more used. Not so efficient and flushes as side effect.

Mechanism of action: improve HDL secretion and reduce VLDL productionin the liver.

Question 14

Ezetimibe

Answer 14

Mechanism of action: inhibitor of cholesterol absorptio form the intestine, by inhibiting directly the transporter NPC1L1.

Indication: primary intervantion as an add-on therapy when statin alone do not reach target levels.

Side effects: abdominal discomfort or diarrhea, steatorrehea-> preblems in absorbing cholesterol-like drugs and liphophilic vitamins (A, D, E, K)

Question 15

Resins

Answer 15

Bile acid sequestrants.
E.g. Cholesteramine.
Need for more bile acids -> increase conversion from cholesterol to bile acids and thus LDL receptors are increased.

Side effects: lipidic drugs and nutrients will be less absorbed. Gi related side effects.

Question 16

Fibrates

Answer 16

Reduce tryglyceridemia by acting through nuclear transcription to decrease ApoC3 concentration -> increase LPL activity.

Question 17

PSCK9 inhibitors

Answer 17

Evolucumab
Potent therapy, approved for secondary prevention in addition to high dose statins

Side effects: myalgia, injection-site reaction

Question 18

Future therapy

Answer 18

Gene therapy via Antisense Nucleotides.

Very safe, high specificity.