lipid metabolism Flashcards
What is the solubility of lipids like?
insoluble or sparingly soluble in water
What are the uses of lipids?
- Lipids are important for synthesis and maintenance of biological membranes
- Also good energy sources
-Also important as the precurser of a number of steroid hormone particles.
The commencement of all steroid hormone particles is cholesterol
How are lipids transported in the blood?
Via lipoproteins
What is cardiovascular disease strongly associated with?
elevated LDL, decreased HDL
What are the causes of elevated LDL and decreased HDL?
diet/lifestyle, gentic factors
What do lipoproteins consist of?
-hydrophobic core and hydrophilic coat
What is found in the hydrophobic core?
estrified cholesterol and trigylicerides
What is found in the hydrophobic core?
monolayer of amphipathic cholesterol, phospholipids and one, or more apoproteins
What are the major lipoproteins (in order of size)?
- HDL particles
- LDL particles
- VLDL
- chylomicrons
What are the two roles of lipoproteins?
-deliver cholesterol and triglyceride to peripheral tissue
OR
-return cholesterol and triglyceride to liver
What is meant by the exogenous pathway?
Absorption and distribution of lipids to the periphery by chylomicrons formed in intestinal cells
What is meant by the endogenous pathway?
Lipids are synthesised by the liver (triglycerides especially) They are then delivered from the liver to peripheral tissues via LDL
How is ApoB48 formed?
Stop codon in the gene produces a smaller mass ApoB in the intestine than in the liver.
What is the life cycle of ApoB containing liposomes?
- assembly
- intravascular metabolism
- receptor mediated clearance
How does triglyceride enter enterocytes?
- we eat foods containing triglycerides
- triglycerides are split into monoglyceride and fatty acids.
- these enter the enterocytes via diffusion where they are converted back into triglyceride.
How does cholesterol enter enterocytes?
Niemann-Pick C1-like 1 protein
(NPC1L1) binds to cholesterol, moves it into the cell and then releases it. Cholesterol is esterified to form a cholesterol ester.
What are enterocytes?
cells that line the intestine
How are chylomicrons assembled?
- As triglyceride droplets form, apoB48 protein is added to them.
- Lipidation occurs using Microsomal triglyceride transfer protein.
- ApoB48 lipoprotein then forms a shell.
- Cholesterol and apoA1 gets added.
- The end product is a mature chylomicron.
- Chylomicrons enter into systemic circulation
What are VLDL particles made up of?
-triglycerides and free fatty acids
Where are VLDLs assembled?
liver hepatocytes
Where do the free fatty acids in VLDLs come from?
-de novo synthesis
OR
-adipose tissues
How does activation of chylomicrons and VLDL occur?
-apoC2 is liberated from HDL and is incorporated into the shell of VLDL and chylomicrons.
What is the role of ApoCII in intravascular metabolism?
ApoCII facilitates the binding of chylomicrons and VLDL particles to Lipoprotein lipase enzyme.
What is the role of Lipoprotein lipase in intravascular metabolism?
LDL etabolises core triglycerides to release them.
What are chylomicron and VLDL remnants?
Particles with cholesterol but without triglyceride are termed chylomicron and VLDL remnants
How are ApoB containing lipoproteins cleared?
- chylomicrons and VLDL dissociate from LPL
- ApoCII is transferred to HDL particles in exchange for apoE
- Particles are now remnants
- remnants metabolised by hepatic lipase in liver
- remnants cleared by receptor mediated endocytosis into hepatocytes
- remaining apo100 remnants become LDL particles lacking apoE and retaining doley apo100
What are apoE?
a high affinity ligand for receptor mediated clearance.
What percentages of apoB48 and apoB100 are cleared by receptor mediated endocytosis into hepatocytes?
All apoB48-containing remnants and 50% of apo100 containing-remnants
What is clearance of LDL particles dependant on?
LDL receptor expressed by liver and other tissues
What causes the uptake of LDL particles?
receptor mediated endocytosis
How is cholesterol released?
Within the cell at the lysosome, cholesterol is released from cholesteryl ester by hydrolysis
What does the release of cholesterol cause?
- inhibition of de novo cholesterol production via HMG-CoA reductase
- storage of cholesterol as cholesterol ester
How is atherosclerosis initiated?
dysfunction and injury of the lining of blood vessels
What are the risk factors of atherosclerosis?
diabetes, high BP, smoking
How does atherosclerosis progress?
- uptake of LDL from blood into intima of artery
- LDL oxidised to atherogenic oxidised LDL
- monocytes migrate into intima and become macrophages
- OXLDL uptake by macrophages which converts them to cholesterol-laden foam cells that form a fatty streak
- division and proliferation of smooth muscle cells by inflammatory substances. Collagen deposition
- athermanous plaque formation.
What is an athermanous plaque made of?
a lipid core (product of dead foam cells) and a fibrous cap (smooth muscle cells and connective tissue)
What is the only organ able to eliminate cholesterol from the body?
liver
What is HDLs role in cholesterol removal?
Mature HDL accepts excess cholesterol from the plasma membrane of cells (e.g. macrophages) and delivers cholesterol to the liver, known as reverse cholesterol transport, by several mechanisms
Where is HDL formed?
liver
What is HDL before it matures?
ApoA1 in association with a small amount of surface phospholipid and unesterified cholesterol (pre--HDL)
What is mature HDL like?
Disc-like pre-HDL matures in the plasma to spherical alpha-HDL as surface cholesterol is enzymatically converted to hydrophobic cholesterol ester that migrates to the core of the particle
What happens when HDL reaches the liver after collection of cholesterol?
HDL reaching the liver interacts with a receptor (scavenger receptor-B1, SR-B1) that allows transfer of cholesterol and cholesteryl esters into hepatocytes
What is the role of cholesterol ester transfer protein?
mediates transfer of cholesteryl esters from HDL to VLDL and LDL, indirectly returning cholesterol to the liver
What is primary dyslipidaemia?
Too much cholesterol caused by a combination of diet and genetic factors
What is secondary dyslipidaemia?
Too much cholesterol a consequence of other diseases (e.g. type II diabetes, hypothyroidism, alcoholism, liver disease)
How affective as statins?
– very effective in reducing total and LDL cholesterol (up to 60%), decrease triglycerides (up to 40%) and modestly increase HDL (about 10%)
What are two examples of statins?
simvastatin and atorvastatin
How do statins work?
They inhibit HMG-CoA reductase which reduces cholesterol synthesis. This causes an increase in LDL receptor expression and enhanced clearance of LDL
What are other benefits of statins?
- Decreased inflammation
- Reversal of endothelial dysfunction
- Decreased thrombosis
- Stabilization of atherosclerotic plaques
When are statins given?
Orally at night
What are the adverse effects of statins?
Adverse effects are few but include myositis and rarely rhabdomyolosis incidence of which is increased if statin is combined with a fibrate
What are fibrins?
Lipid lowering drugs
How effective are fibrates?
- decrease in triglycerides (up to 50%)
- decreases (up to 15%) in LDL
- and increases (up to 20%) in HDL,
What are examples of Fibrates?
bezafibrate and gemfibrozil
What are fibrates first line in treateing?
patients with very high triglyceride levels
How do fibrates work?
Act as agonists of a nuclear receptor (PPAR) to enhance the transcription of several genes, including that encoding LPL
What are the adverse effects of fibrins?
Have few adverse effects, but like statins may rarely cause myositis – combination with latter is generally inadvisable. Best avoided in alcoholics who are predisposed to hypertriglyceridaemias, but also rhabdomyolosis
-Incidence of other adverse effects (G.I. symptoms, pruritus and rash) greater than for statins
