Lecture 16 Atherosclerosis II Flashcards Preview

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How are lipids transported in the body and why

As lipids are hydrophobic they are transported in the body as lipoproteins


Outline the general structure of a lipoprotein

Consist of a central core of hydrophobic lipid such as a triglycerides or cholesterol surrounded by a hydrophilic coat of phospholipids free cholesterol and apolipoproteins


How are lipoproteins classified

Lipoproteins are classified according to density each has a decreasing amount of core lipid


Recall the different classifications of lipoproteins

HDL IDL LDL VLDL and chylomicrons


Below is a table with a list of the different classifications of lipoproteins their diameter and the apolipoproteins contained. Draw a line to match up the lipoprotein with its diameter and constituent apolipoprotein

See completed table


What are the three pathways involved in lipid transport and outline the direction of transport

Exogenous (dietary) – from food to tissues. Endogenous – from liver to tissues. Reverse cholesterol – cholesterol from tissues to the liver for excretion


Explain the exogenous or dietary lipid transport pathway

Ingested lipids are broken down in the stomach to their individual lipid molecules. These lipid molecules are then transported out of the digestive system by the NPC1L1 transporter before they make their way into the lymphatic system. Here they are packaged with ApoB-48 into a nascent chylomicron which then travels through the lymphatic system to the liver where it moves into the blood stream and interacts with HDL. HDL donates ApoC and ApoE to the nascent chylomicron which now forms a mature chylomicron. This mature chylomicron transports itself in the blood stream until it finds adipose tissue which it interacts with via ApoC. This leads to the activation of lipoprotein lipase in the adipose tissue which hydrolyses the chylomicron to release the cholesterol and fatty acids contained in the centre of the molecule. These cholesterols and fatty acids are now accessible by tissue which will then absorb and use the molecule. After being hydrolysed the now remnant chylomicron will continue round the blood stream until it reaches the liver and is taken up by ApoE or ApoB-48 which bind to receptors in the liver. The chylomicron may then further hydrolyse to release cholesterol which may then be either stored oxidised and converted into bile acids or packaged into VLDL.


Explain the endogenous lipid transport pathway

In the liver triacylglycerol and cholesterol are assembled with ApoB-100 to form VLDL which then receives ApoC-II and ApoE donated by HDL. VLDL can circulate in the blood stream until ApoC-II activates lipoprotein lipase (LPL) in the tissues leading to the hydrolysis of the VLDL and the release of glycerol and fatty acids these are then absorbed by adipose tissue and muscle. The hydrolysed VLDL is now referred to as IDL which returns to the liver and is further hydrolysed to LDL by hepatic lipase releasing more glycerol and fatty acids. This LDL can then go one of two ways; it can bind to tissues via ApoC and become internalised before being hydrolysed in lysosomes to release yet more cholesterol. Alternatively LDL binds to the LDLR in the liver via ApoB-100 and is removed from the circulation


Explain the reverse cholesterol transport pathway

The reverse cholesterol pathway removes cholesterol from peripheral tissues and returns it to the liver. ApoA1 on the HDL molecule binds to transport proteins ABC-A1 or ABC-G1 that are found on macrophages/foam cells in the atherosclerotic lesion and adsorbs cholesterol. HDL can then transport cholesterol to liver via either the indirect pathway or the direct pathway. In the indirect pathway cholesterol esters are transferred to VLDL and LDL particles via cholesterol ester transport protein (CETP). LDL then binds to LDLR in the liver and is taken up. Alternatively in the direct pathway ApoA1 from HDL binds the SRB1 receptor in the liver and cholesterol is transferred. HDL is then free to recirculate back to collect more cholesterol. Cholesterol in liver is processed and secreted in bile or transported to intestine via ABC-G5/G8 for excretion


What is meant by the term dyslipidaemia

An abnormal amount of lipids in the blood


Most dyslipidaemias are what kind

Hyperlipidaemias where there is an elevation of blood lipids


Dyslipidaemias can be primary or secondary how do they differ

Primary dyslipidaemia is a combination of diet and genetics and is usually polygenic. Secondary dyslipidaemia on the other hand is a consequence of other conditions such as diabetes alcoholism chronic renal failure liver disease and administration of drugs. These secondary dyslipidaemias are treated where possible by correcting the underlying cause


What is the Frederickson classification of dyslipidaemias

The Frederickson classification classifies primary dyslipidaemias into 6 phenotypes based on which lipoprotein particle is abnormal.


The higher the LDL and the lower the HDL the higher the risk of atherosclerosis and IHD T or F



Quite a few of primary dyslipidaemias don’t really influence atherosclerosis as they are affecting different lipoproteins T or F



Which is the main classification of dyslipidaemia relevant to atherosclerosis

Type II dyslipidaemia increases the risk of atherosclerosis as it significantly increases LDL levels in the blood. This dyslipidaemia is also known as familial hypercholesterolaemia


What is familial hypercholesterolaemia

A genetic disorder causing very high LDL levels in the blood and early cardiovascular disease


Patients which familial hypercholesterolaemia usually have mutations in which genes

LDLR or ApoB


Although most mutations are in LDLR or ApoB most FH is thought to be polygenic T or F



Most FH patients are homozygous for mutations in the LDLR gene T or F

F – they are heterozygous and this occurs in 1:500 people


How is FH treated in heterozygous patients

Normally treated with statins bile acid sequestrants or other lipid lowering agents that lower cholesterol levels


How do the symptoms of FH differ in homozygotes

Patients homozygous for the LDLR mutation can have severe CVD in childhood. These patients often do not respond to medical therapy and may require other treatments


How is FH treated in homozygous patients

LDL apheresis (removal of LDL from the blood) and occasionally liver transplantation


What is the incidence of homozygous FH

1 in 1 million


What is the overall treatment strategy in dyslipidaemia and atherosclerosis

Drug therapy aimed at reducing levels of LDL combined with dietary changes


What are the main classes of drugs available for the treatment of atherosclerosis

Statins fibrates cholesterol absorption inhibitors and PSCK9 inhibitors


What is the most commonly used treatment of dyslipidaemias



How do statins act

Statins act by inhibiting the conversion of HMG-CoA to mevalonic acid. HMG-CoA reductase is a rate-limiting enzyme in cholesterol synthesis hence you can regulate cholesterol levels by targeting HMG-CoA reductase


List some of the specific reversible competitive statins

Simvastatin lovastatin and pravastatin


List some of the longer-lasting statins

Atorvastatin rosuvastatin