Lipid metabolism

What lipoprotein is a major contributor to atherosclerosis?

LDL

What is the structure of lipoproteins?

Hydrophobic core and surface monolayer of phospholipid

What is the structure of lipoproteins hydrophobic core?

Cholesterol fatty acid ester, also contains a triacylglycerol - glycerol and 3 acid groups that are insoluble in water

What is the structure of the monolayer of phospholipids?

Amphiphatic - allows blood transport, hydrophobic tails and hydrophilic/polar head groups

What is the name of an amphipathic surface proteins and is a ligand for lipoprotein receptors?

Apolipoprotein

What is the order of lipoproteins in order of most fatty and least dense to least fatty and most dense?

HDL > LDL > VLDL > Chylomicron

How are cholesterol and triglycerides packaged from the intestine?

Interact with bile to form micelles

What happens to the micelles containing triglycerides and cholesterol?

Triglycerides broken into free fatty acids, diacylglycerides, monoisoglycerol and cholesterol broken into esters

What is the process from when cholesterol and triglycerides are broken down from micelles to usage in muscle?

• Absorbed into small intestine and made back into triglycerides and cholesterol and into chylomicrons

• APOB48 is attached to the chylomicron

• ApoCII attaches to chylomicron and works as a marker/ligand for lipoprotein lipase

• ApoCII attaches to lipoprotein lipase which hydrolyses triglycerides into free fatty acids for the tissue/muscle to use to make ATP

How can triglycerides and cholesterol be used from the liver to lipoprotein lipase?

• Liver synthesises cholesterol naturally

• Packages triglycerides and cholesterol into VLDL particles

• Attaches APB100 and ApoCII and sends to lipoprotein lipase

• Used in muscle as ATP

What happens to free fatty acids and cholesterol when 50% has been used?

• Particle release from muscle and interacts with HDL containing ApoE

• Exchanges APOC2 from particle exiting lipoprotein lipase for ApoE

• ApoE is a good ligand for LDR - low density lipoprotein receptor and absorbed into liver

• Good process to regenerate ApoC2

What happens to molecules containing ApoB48 when metabolised by the liver?

Metabolised by the liver well

What happens to molecules containing ApoB100 when metabolised by the liver?

• Either attached to HDL with ApoE remnant

• Incompletely metabolised triglycerides and Abo48 without ApoE released into LDL

• Absorbed into blood vessel where it sneak sunder the endothelial lining

• Targeted may macrophages which ingest and become foam cells, causes necrosis

• Necrosis causes an inflammatory response leading to atherosclerosis

What are some characteristics of ApoB48?

Long half life, poorly reabsorbed, full of cholesterol

What cholesterol is known as good cholesterol?

HDL

What is the link between CVD and cholesterol levels?

Elevated LDL and low HDL associated with CVD

What is the term to describe elevated cholesterol?

Hypercholesterolaemia

What does a low ratio of LDL/HDL slow?

Slows atherosclerosis

What is the term to describe elevated triglycerides?

Hypertriglyceridaemia

What can the cause of hyperlipidaemia be?

Familial or diet related

What are some risk factors for hyperlipidaemia?

Smoking 2x increases CAD, diet and obesity increases MI risk, hypertension and diabetes increases risk

What is the type of prevention which is done before clinical evidence of a disease is found?

Primary prevention

What patients should have their serum cholesterol measured?

Family history of arterial disease, obesity, diabetes, hypertension

What is the type of prevention for treatment after evidence of vascular disease present/after a coronary event?

Secondary prevention

What is the rate limiting step in cholesterol synthesis?

HMGCoA to mevalonate

Where do statins act?

HMG CoA reductase - reduces HMGCoA to mevalonate usually

What is the first pathway in cholesterol synthesis?

Mevalonate pathway

What is the feedback regulation pathway for cholesterol?

High cholesterol downregulates the pathway and turns on synthesis via SREBP, low cholesterol does the opposite

What is a key molecule in cholesterol synthesis?

Squalene, lanosterol

What is the evidence behind statins use in CVD?

Reduce mortality after MI and in absence of obvious CVD

What is the MOA of statins?

Inhibit cholesterol synthesis - decreases liver cholesterol, activates SREBP, increases expression of LDL receptor and increases its uptake so plasma cholesterol is decreased so less plagues

What are some examples of statins?

Simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin

What statins MUST be taken at night due to their shorter half life and cholesterol synthesis occurring mostly at night?

Pravastatin, Simvastatin, fluvastatin

What are the ADRs of statins?

Some myopathy at high doses - muscle pain, stiffness and can progress to rhabdomyolysis

What blood level can be monitored to see if rhabdomyolysis is occurring?

Creatine kinase

What increases the risk of rhabdomyolysis in statins?

Renal insufficiency, co-treated with fibrates or ciclosporin

What are the cautions and CI of statins?

Caution in patients at risk of myopathy, CI in liver disease, pregnancy, breastfeeding

Why are statins CI in liver disease?

All metabolised by liver and work in the liver

What is the effect of CYP inducers being used with statins?

increased statin metabolism, potential treatment failure

What is the effect of CYP inhibitors being used with statins?

Reduced statin metabolism and causes ADR - prevents activation

How do bile acid binding resins work?

Decreased reabsorption of bile via enterohepatic recycling and increase excretion, increase bile synthesis and decrease liver cholesterol, increasing LDL receptor expression and decreasing plasma cholesterol

What are some examples of bile acid binding resins?

Cholestyramine, colestipol

What are the ADRs of bile acid binding resins?

Limited because not absorbed, GI - constipation, bloating, flatulence

What are the cautions of bile acid binding resins?

Can bind vitamin A, D, K and supplements may be needed, can bind certain drugs and reduce bioavailability e.g., warfarin, digoxin, some statins, thiazide, aspirin - take other drug 1 hour before or 4 hours after resin

What are some drawbacks to bile acid binding resins?

Inconvenient to take and gram doses

How does ezetimibe work?

inhibits transport of cholesterol across intestinal brush order, decreases cholesterol in chylomicrons, liver, VLDL and LDL and upregulates LDL receptor further reducing plasma cholesterol

What are the cautions and CI of ezetimibe?

Hepatic impairment, CI in breastfeeding

What are the ADRs and interactions of ezetimibe?

GI disturbances e.g., diarrhoea and abdominal pain, interact with fibrates and plasma conc increases

How do plant sterols e.g., margarine-like spreads work?

Displace cholesterol from micelles so excreted not absorbed but large quantities need to be effective

How do fibrates work?

Activate PPAR alpha transcription factor which decreases plasma triglyceride, increases HDL apolipoproteins which increases cholesterol clearance, increasing lipoprotein lipase,fatty acid uptake and oxidation to decrease triglycerides

What are some examples of fibrates?

Bezafibrate, ciprofibrate, fenofibrate

What are the cautions and CI of fibrates?

Myotoxicity, especially in renal disease, displaces warfarin from plasma proteins, CI in hepatic/renal impairment as can cause myopathy, pregnancy and breastfeeding

What are the ADRs of fibrates?

GI disturbances e.g., nausea, can cause anorexia, can cause myopathy when combined with statin

What is an example of a PCSK9 inhibitor?

Alirocumab, evolucumab

How do PCSK9 inhibitors work?

Inhibit PCSK9 which will increases LDL-R in liver cells and promote LDL clearance

How does nicotinic acid work?

precursor of NADP - increases HDL and decreases lipolysis in adipose tissue, decreases flux of free fatty acid to liver and decreases production of VLDL and LDL, inhibits triglyceride synthesis

What are the ADRs of nicotinic acid?

Flushing and pruritis/itching due to prostaglandin release and vasodilation - limits use, diarrhoea, nausea, vomiting, Hyperuricaemia inhibits uric acid secretion, reduced insulin sensitivity so can cause diabetes and gout

What can be used to treat flushing and pruritis relating to nicotinic acid?

Aspirin

What are the cautions and CI of nicotinic acid?

unstable angina, MI, diabetes, gout, CI in arterial bleeds, peptic ulcer disease, breastfeeding

What do omega-3 fatty acids do?

Reduce triglyceride biosynthesis but unsure if decreases risk of CVD

Where are omega-3 fatty acids found?

Fish e.g., salmon, halibut or supplements

What is the recommendations around omega-3 fatty acids?

DO NOT advise patients to use