Hyperlipidemia

Question 1

What is Hyperlipidemia ?

Answer 1

Umbrella term - elevated level of lipids in the blood.
Includes :

Hypercholesterolaemia - elevated cholesterol

• Hypertriglyceridemia - elevated triglyceride

These can happen in isolation or together - most often happens together

together - mixed/ combined hyperlipidemia.

CAUSES

0 Primary - genetic ( gene causing over production of lipids or reduced clearence

0 Secondary - excessive fat intake in diet - trans fate etc.

Question 2

How are lipids stored and transported ?

Answer 2

Storage - stored as lipid droplets

Transport - lipids transported in complex with protein

e. g
- HDL - High density Lipoprotein - mean high proportion of lipid compared to lipid.

LDL - low density Lipoprotein - high proportion of lipid vs protein

VLDL - very low density Lipoprotein

ULDL - chylomicrons - Ultra low density lipoprotein

this is classification based on density but there are variations in shape, charge size etc.

Question 3

What are apolipoproteins?

Answer 3

proteins that bind to lipids to form lipoproteins

involved in transport of lipids,

Question 4

Pathways of VLDL , LDL (Lipoprotein )synthesis ?

Answer 4

dietary triglycerides / stored triglycerides from adipose tissue/ stored cholesterol & cholesterol made by liver ——–> triglycerides cholesterol packaged into VLDL.——> VLDL released into circulation ——–> lipoprotein lipase released by surrounding tissue and attaches to blood vessel —–> VLDL bumps into blood vessel walls ——> VLDL attaches to Lipoprotein Lipase ——> lipase breaks down lipids ——> free fatty acids released locally into tissue —–> fatty acid binds to fatty acid receptor ——-> fatty acid taken by cell to use.

( as lipid is broken down VLDL changes to LDL as lipid component decreasing in comparison to protein. )

• as newly converted LDL it is richer in cholesterol as fatty acids have been released . It keeps circulating until it is taken up by tissues that need cholesterol

LDL receptor on the cell binds to lipoprotein and the the lipoprotein is engulfed by endocytosis.

Question 5

Pathways of HDL (Lipoprotein )synthesis ?

Answer 5

dietary triglycerides , cholesterol etc . ( HDL - more protein content is packaged vs in VLDL & LDL ) ——> HDL binds via its apoproteins to ABCG1 ( ATP binding cassete G1 ) ——> Triglycerides & cholesterol offloaded and travel through channel ——-> Reverse cholesterol transport occurs - Cholesterol released from HDL travels to ABCG1 and travel back the opposite way through ABCG1.
(This is the difference with HDL Carries lipids to tissues but carries cholesterol away (from blood vessel walls , tissues etc) to liver. )

CETP - enzyme which facilitates HDL giving LDL cholesterol (that it has picked up ) in exchange for triglycerides.

Question 6

What is the meaning of bad LDL and good HDL ?

Answer 6

bad LDL - increased disease risk - cardiovascular risk.

Good HDL - decreased disease risk - decreased cardiovascular risk .

• note - cholesterol is not bad - you need it for certain cellular processes e.g lipid bilayer. However, it is when the supply of cholesterol is greater than the body needs and can be metabolised.

Question 7

Hyperlipidaemia treatment ?

Answer 7

Lifestyle adaptation -

0 dietary modification

0 Physical exercise.

If not enough :

Statins

inhibit HMG - CoA - reductase needed in the synthesis of cholesterol——> cholesterol goes down.

Cholesterol levels linked to LDL receptor expression.

Lower levels of cholesterol —> raised level of LDL receptor —–> more LDL cleared from blood and taken up by liver.

triglycerides also taken out of the blood as LDL contains both cholesterol and triglyceride.

if statin not tolerated or not enough :

Ezetimibe

inhibits uptake for cholesterol by inhibiting NPL1CL channel on enterocytes and hepatocytes which take up cholesterol.

: in enterocytes - cholesterol taken up and forms chylomicrons

ezetimibe - only affect cholesterol take up - from evidence

Evolocumab - (when used with statin - reduced LDL cholesterol further )

inhibit PCSK9 - (blocks recycling of LDL receptors )

Lomitapide - used in specific cases if all others therapy failed e.g genetic cause - familial hypercholesterolemia.

Question 8

How do chylomicrons transport lipids ?

Answer 8

ULDL - ultra low density Lipoprotein .

triglycerides & cholesterol absorbed from small intestine ——-> enterocytes packages it into chylomicrons.