Lipids Flashcards
What are the four pathways for lipid transport?
- Exogenous: gut–> periphery, via chylomicrons - Endogenous: liver–> periphery, via VLDL - Reverse: periphery –> liver: via HDL - Bile production: liver –> digestive tract
What lipoproteins transport fat in the exogenous pathway, and where are they taken up?
- small intestine packages lipids as chylomicrons - taken up by the liver
What lipoproteins transport fat in the endogenous pathway, and where are they taken up
- packaged into VLDL - taken up in the periphery
What lipoproteins transport fat in the reverse cholesterol transport and where are they taken?
- packed into HDL - taken up by the liver
Where in the periphery are most lipids stored and used?
- stored in adipose tissue - and muscle tissue
What are the conditions for reverse cholesterol transport?
- occurs when the lipid supplies in the liver are being diminished - this is a sign of reduced body lipid
GIve an overview description of bile production and recycling
- Bile produced from cholesterol in the liver - released into the gut and gall bladder via the cystic duct - most bile acids are absorbed in the gut and returned to the liver
What is the main function of lipoprotein lipase?
- metabolises triglycerides so they can be removed from VLDL and moved to capillary membrane of blood vessels - triglycerides –> fatty acids + glycerol - cell surface linked enzyme in the capillary walls
What are apolipoproteins and what do they do?
- amphipathic lipid-carrying protein in lipoprotein particles - allows lipids to be transported as they are not soluble in plasma
Explain why big lipoprotein particles have lower density compared to smaller lipoproteins
- lipids hav e alower density than proteins - larger lipoproteins have more triglycerides than smaller ones - smaller lipoproteins tend to have more cholesterol and proteins - therefore larger lipoproteins are less dense
Why is Low Density Lipoprotein the most dangerous?
- LDL can store blood cholesterol that can not be stored elsewhere , largest store of cholesterol esters
- therefore LDL is an indicator of excess lipids in the body being transported to the liver from the periphery
- Excess LDL and its content i.e cholesterol esters can accumulate in atheromas, hence the beginnings of atherosclerosis
Why is High Density Lipoprotein an indicator of cardiptection?
- lipids being moved form the periphery to liver in reverse cholesterol transport - HDL is an indicator of low lipid states - occurs when cholesterol is being consumed
Why does Very Low Density Lipoprotein indicate a risk of atherogenesis?
- VLDL is transports triglycerides and endogenous cholesterol from the liver to adipose and muscle tissue - in the periphery triglycerides are removed from VLDL forming IDL - this is an intermediate to LDL
What is Intermediate Density Lipoprotein?
- it is the lipoprotein formed after triglycerides have been removed from VLDL - this then becomes LDL
What does a chylomicron do?
- it transport triglycerides and fatty acids (exogenous lipids) from the gut to the periphery - elevated after eating fatty meals - not usually an indicator of CV risk
Give two endocrine cell types in the pancreas, and describe their primary secretion
- Beta cells: secrete Insulin at high blood glucose levels - Alpha cells: secrete Glucagon at low blood glucose levels
What is the action of Insulin and Glucagon?
- Insulin stimulate adipocytes to absorb glucose - Glucagon stimulates the liver to release glucose both act in order to normalize blood glucose levels
What is Type II diabetes and what causes it?
- relative insulin deficiency, caused by insulin resistance - a reduction in adipocyte absorption of glucose - results in high levels of circulating glucose - aka adult onset diabetes
What is hypercholesterolaemia and what causes it?
- high plasma cholesterol levels - environmental and genetic factors
What drugs are used to treat hypercholesterolemia and how do they work?
- Statins - block endogenous cholesterol synthesis by blocking HMG-CoA Reductase: this is the beginning step to cholesterol synthesis
What is metabolic syndrome?
- a cluster of related CVD risk factors - including, high BP, high fasting glucose, high LDL cholesterol, low HDL cholesterol, high triglycerides - associated with insulin resistance and central obesity (apple vs pear)
alongside the other 2 steps
What is Beta oxidation?
- the pathway from fatty acids to Acetyl-CoA - takes place in the mitochondrion, and peroxisomes - releases free energy, successive removal of 2-carbon fragments
What is Lipogenesis?
- the pathway from Acetyl-CoA to fatty acids
- process depends on fatty acid synthase
- the Acetyl CoA needs to be made into citrate first
- occurs in the cytosol - Acetyl-CoA + ATP + e –> fatty acid +CO2 + CoA
What is Acetyl-CoA and give its uses?
- it is a mediating molecule in the krebs cycle - used as an energy mediator - can be used to form ketone bodies in the mitochondrion - can be used to form cholesterol
What is fat mobilization?
- when fatty acids are released from adipose tissue in times of stress in order to release energy - fatty acids are shortened by 2 carbons at a time to produce ATP + Acetyl-CoA
What are the uses of cholesterol?
Acts as a precursor to - bile acids - steroid hormones - Vitamin D Provides structure and stability to cell membrane
General Cholesterol facts
- obtained from the diet or the liver
- it is heavily recycled due to high metabolic cost to produce it seen in bile salts and the endogenous pathway sometimes partially soluble due to the OH group
- it is amphipathic
- stored in most tissues as cholesterol esters, makeing it very insoluble
What are cholesterol esters?
- cholesterol molecules that have bonded with a fatty acid
- formation is catlaysed by ACAT (acetyl-CoA transferaase)
- hydrolysed by lipases to reform its reactants 75% of plasma cholesterol
- 43% cholesterol linoleate
- 23% cholesterol oleate
Give examples of steroids
- Cholesterol - Vitamin D (sort of) - Cortisol: by the adrenal cortex - Testosterone
What are ketone bodies?
- water soluble molecules containing the ketone group that are produce in the liver from Acetyl-CoA breakdown during fasting - they last 5 hours, if they aren’t used they will be lost - act as a major energy source for the brain and heart
Give two examples of ketone bodies and a brief life cycle
Acetoacetic Acid & beta-hydroxybutyric acid - these two spontaneously breakdown if they are not used - through decarboxylation acetone is formed - this is then eliminated by the kidney as waste
What is ketogenesis?
this occurs when acetyl-CoA cannot enter the citric acid cycle during starvation - usually when more acetyl-coA is produced than can be processed by the citric cycle
What is the importance of unsaturated fatty acids
- increases the fluidity of cell membranes most naturally occuring FA are cis - they form a kink in the carbon backbone - interferes with the phospholipid bilayer - less likely to form a solid matrix
What are the 3 steps and products in Beta Oxidation?
1) activated by Coenzyme A in the cytosol forms Acyl-CoA, synthesised by acyl-coA dehydrogenase, FAD into redFAD
2) allows the fatty acid to be transported across the mitochondrial membrane
3) progressive oxidation of fatty acids along the carbon chain
- produces 1 FADH2 , 1 NADH molecule
How are short-chain fatty acids transported?
- in albunin molecueles
How does CoA get out of mitochondria?
What occurs in the citrate malate cycle?
- Acetyl-CoA converted to citrate for transport out of the mitochondria then back to acetyl CoA in the cytosol for use in the fatty acid synthesis
- the Oxaloacetate produced is then converted back to pyruvate for transport back into the mitochondria for use in ATP synthesis
Where does fatty acid synthesis take place?
- liver and adipocytes
- occurs in the cytosol
- derived from acetyl-CoA from the mitochondria
What are the steps for cholesterol biosynthesis?
- Acetyl CoA →HMG-CoA –HMG-CoA reductase →Mevalonate → squalene → cholesterol
What enzyme hydrolyses TG on digestion after emulsification?
- Pancreatic Triacylglycerol Lipase
Go through the lipid transport system
- Chylomicrons: deliver dietary TGs to muscle and adipose tissue + dietary cholesterol to the liver
- VLDL: transport endogenous TGs and cholesterol
- LDL: transport cholesterol from liver to tissues
- HDL: transport cholesterol from tissues to liver i.e. remove cholesterol from tissues
How are lipids taken up by cells?
- Chylmicrons and VLDL particles give up TG to tissues by the action of tissue-bound lipases
- liver recognises remnants of these particles by their ApoE content and takes them up for re-cycling
- LDL particles contain ApoB-100 which is recognized by cell surface LDL receptors (LDLRs)
Explain the regulation of LDL receptors
- down-regulated by PCSK9: proprotein convertase subtilisin/Kexin type 9
- up-regulated by SREBPs: sterol regulatory element-binding protein
What are the major CVD risk factors found in the Framingham Heart Study?
- High blood pressure
- High blood cholesterol
- Smoking
- Diabetes
- Sedentary behaviour/ inactivity
- Obesity
Who would be given primary lipid modification prevention, and what does this treatment entail?
- those with no previous history of CVD and
- a QRISK2 > 10%
- Statin: Atorvastatin 20 mg
Who would be given secondary lipid modification prevention, and what does this treatment entail?
- those with a history of CVD
- Statin: Atorvastatin 80 mg
What is Ezetimibe and what is its effect?
- a potent and selective inhibitor of absorption of cholesterol in the SI
- reduces the contribution of dietary and biliary cholesterol
- therefore reduces the flux of cholesteryl esters into VLDL particles
- 10mg/day induces a 20% reduction in LDLC and 8% reduction in TG
What are BIle Acid Sequestrants (Resins) and what is their effect?
- side effects?
- they bind bile acids in the intestine, interrupting the enterohepatic circulation of bile
- causes increased conversion of cholesterol into bile acids in the liver
- treatment limited by constipation and flatulence, older resins cause oesophageal irritation
What are Fibrates and what is their effect?
- they lower blood cholesterol, triglyceride reduces by 25-50% and increase HDL-C by 15-25% they:
- increase peripheral lipolysis by activating lipoprotein lipase
- decrease hepatic triglyceride production
- modulation of LDLR/ligand interaction
- they stimulate reverse cholesterol transport
What is Omega 3 and what is their effect?
- fish oils
- they inhibit lipogenesis and stimulate beta-oxidation (conversion of triglycerides to acetyl-CoA which can enter the TCA cycle)
- reduces the rate of secretion of VLDL triglyceride
- shown to significantly reduce the risk for sudden death caused by cardiac arrhythmias and all-cause mortality in patients with known coronary heart disease
What is PCSK9 and what is their effect?
- they are binding proteins, primarily expressed in hepatocytes,
- they bind to LDL-Receptors and promote the receptor degradation after they have been endocytosed alongside the LDL particles
- this reduces the number of LDLR on the cell surface membrane
- therefore reduces the number of LDL particles that can be removed from circulation
What is the action of PCSK9 inhibitors?
- inhibit the action of PCSK9 binding proteins on LDL-receptors
- this reduces the amount of LDLR degradation
- this increase the number of LDLR on cell surface membranes and increase the number of LDL particles that can be removed from circulation
What is the lipoprotein pattern of abnormality seen in Hypercholesterolaemia?
- raised total cholesterol and LDL
- usually seen in familial hypercholesterolemia where total cholesterol levels range between 7-20mmol/L in heterozygotes or higher in rare homozygous between 15-30mmol/L
What is the lipoprotein pattern of abnormality seen in Mixed hyperlipidemia (dyslipidemia)
- raised total cholesterol and LDL with raised TG and often low HDL
- seen in patients with glucose intolerance and diabetes
- arises from increased production and reduced breakdown of triglyceride-rich lipoproteins
What is the lipoprotein pattern of abnormality seen in Hypertryglyceridaemia?
- this is less common and ay be familial
- tends to cause harm through acute pancreatitis
What causes Familial Hypercholesterolaemia (FH)?
- Mutations in the LDLR gene that encodes the LDLR protein which reduces its function
- In a few cases (~ 3%) with the same clinical phenotype; it is either a mutation in ApoB which is the part of LDL that binds with the receptor, or
- a gain of function mutation in LDL receptor degradation (PCSK9).
What are the clinical presentations of Familial Hypercholesterolaemia (FH)?
- Tendon Xanthoma (knuckles and Achilles tendon)
- Corneal arcus
- (in homozygous cases bumps of cholesterol deposits can be seen all over the skin)
What would the following symptoms be diagnostic of if seen on an ultrasound scan of the carotid arteries?
- intimal thickening in both carotid arteries
- with intimal calcification and soft plaques in the left internal carotid artery,
- diffuse narrowing of the left vertebral artery with
- reduction in the flow velocity
- Extensive atherosclerosis
What would the treatment be for FH?
- Low Saturated Fat Diet and exercise
- Statins
- Possible addition of cholesterol absorption inhibitor (ezetimibe)
- Rarely resins/surgery/LDL apheresis
- Anti–PCSK9
- Involve patient self-help group, offer DNA testing and get the family tested.
