14 - Hyperlipidaemia and angina

What are all the roles of cholesterol?

Structural cell membrane component / precursor to steroid hormone & bile acids

What are some examples of steroid hormones?

Oestrogen / cortisol

How is bile acid synthesized? + how does it end up in the GI tract?

From cholesterol in liver / secreted into the GI tract via the bile duct.

What % of bile acid is recycled?

95%

How is bile acid reabsorbed and recycled?

Returned to liver via hepatic portal vein & recycled

What must the loss of cholesterol be balanced with?

Cholesterol synthesis

What is the most important step of cholesterol synthesis?

HMG-CoA → mevalonate

What is the catalyst for the reaction: HMG-CoA → mevalonate ?

HMG-CoA reductase

Why is ‘HMG-CoA → mevalonate’ the most important step in cholesterol synthesis?

Is the rate-limiting step in the pathway / control rate of cholesterol synthesis

What is a hepatocyte?

Liver cell

How do hepatocyte use this rate-limiting step to control rate of cholesterol synthesis?

Feedback to regulate the transciption of the HMG-CoA reductase gene and enzyme activity itself.  

What are enterocytes?

Cells lining the GI tract

What is the name of the cholesterol transporter on enterocytes?

NPC1L1

What is the precise location of the NPC1L1 transporter on enterocytes?

On their luminal side

What are chylomicrons?

Class of lipoprotein

How do chylomicrons end up in the bloodstream?

Secreted into the lymphatic system and pass into bloodstream

What are all the classes of lipoproteins? (ABBREVIATION ONLY)

LDL / IDL / VLDL / HDL

What does LDL stand for?

Low density lipoprotein

What does IDL stand for?

Intermediate density lipoprotein

What does VLDL stand for?

Very low density lipoprotein

What does HDL stand for?

High density lipoprotein

What does the core of all lipoprotein contain?

Triglycerides / cholesterol esters

Lipoprotein core structure is organised around proteins called:__________?

Apolipoprotein

What function apolipoproteins enable?

Enable the body to identify which class a particle belongs to / they are molecular ‘address labels’

What class of lipoproteins have ApoB-100 as their apolipoprotein?

LDL / VLDL

What is the specific apolipoprotein in LDL / VLDL’s?

ApoB-100

What class of lipoproteins have ApoA-I & ApoA-II as their apolipoprotein?

HDL

What is the specific apolipoprotein in HDL?

ApoA-I / ApoA-II

Which lipoprotein has the lowest density composition?

Chylomicrons

State all class of lipoproteins from lowest to highest density composition. (include chylomicrons)

Chylomicrons / VLDL / IDL / LDL / HDL

What is the name of one of the most important clinical studies on good/bad cholesterol?

Framingham Heart study / 1948

What was the Framingham heart study about?

Investigated the epidemiology of hypertension and heart disease and provide first evidence for many of the risk factors for CV problem

What was the key finding in the Framingham heart study on cholesterol?

That high lvls of serum cholesterol were linked with CVD

What are the 2 proteins that increase in expression when cholesterol lvls fall?

LDL receptors / PCSK9

What proteins aid transportation of cholesterol released from LDL particles in cytoplasm?

NPC1 / NPC2

What happens when PCSK9 binds to a LDL receptor complex?

If this happens, LDL receptor is not recycled / it will enter a endosome and then a lysosome and degraded into AAs

What disease/disorder is strongly linked to mutation in NPC1?

Obesity

How does LDL receptor mutation lead to excess serum LDL cholesterol?

Mutation in LDL receptor can stop it from recognising apoB-100. This prevent uptake of LDL by liver, causing it to accumulate in the circulation

How does ApoB-100 mutation lead to excess serum LDL cholesterol?

Can alter structure, preventing binding efficiently to LDL receptors. This reduces the ability of the liver cells to clear LDL from the circulation

How does PCSK9 mutation lead to excess serum LDL cholesterol?

Gain of function mutation result in more LDL receptor being sent to lysosome and degraded / less receptor to intake LDL into liver / more LDL accumulate in blood.

What are some physical signs / symptoms of familial hypercholesterolemia?

Xanthelasma / xanthomas

What is xanthelasma?

Yellow deposit of cholesterol around the eyes

What is the name of the condition where you get ‘yellow deposits of cholesterol around the eyes’?

Xanthelasma

What is xanthomas?

Nodules of cholesterol deposited in skin or tendon

What is the name of the condition where you get ‘nodules of cholesterol deposited in skin or tendon’?

Xanthomas

What is atherosclerosis?

Progressive condition by deposition of fatty atherosclerotic plaques (atheroma) in blood vessels

What causes angina?

Ischaemic tissue in the heart / result in chest pain

What happens if atherosclerosis occurs in the brain?

Result in transient ischaemic attack (TIA) / mini stroke that last a few minutes

What happens if the atherosclerosis cause ruptures?

Blood clot can form resulting in myocardial infarction / ischaemic stroke

What happens to the atherosclerotic plaque overtime?

Plaque become fibrous

What is peripheral arterial disease?

Atherosclerosis restricts blood flow to the leg causing claudication

What pain signals are released with cardiac muscles are deprived of O2?

Adenosine / protons / bradykinin / K+

What are the 2 category involving cardiac ischaemia?

Stable angina / acute coronary syndrome (ACS)

What are the 3 types of ACS?

Unstable angina / NSTEMI / STEMI

What does NSTEMI stand for?

Non-ST elevation myocardial infarction

What does STEMI stand for?

ST elevation myocardial infarction

What medication is the main angina medication and can relieve stable angina if rest is ineffective?

GTN / glyceryl trinitrate

What cells are the main components of atherosclerotic plaques?

Foam cells

Why is atherosclerotic considered a chronic inflammatory condition?

Due to involvement of macrophages

What did foam cells start of as?

Immune system cells / macrophages