ChemPath 2S: Lipoproteins Flashcards
What are Atherosclerotic plaques formed of?
- Atherosclerotic plaques are formed of a
- necrotic core (dead macrophages) of cholesterol crystals surrounded by foam cells (macrophages)
- all topped with a fibrous cap
Name some plasma lipoproteins
- Chylomicron (high TGs)
- vLDL (high TGs)
- LDL
- HDL
What are the concentrations in fasting plasma – Cholesterol & Triglycerides of the following plasma lipoproteins:
- Chylomicron (high TGs)
- VLDL (high TGs)
- LDL
- HDL
What are the types of dyslipidaemia?
- hypercholesterolaemia
- hypertryglyceridaemia
- mixed hyperlipidaemia
- hypolipidaemia
Describe cholesterol absorption, metabolism, transport
Describe triglyceride absorption, metabolism, transport
Where is cholesterol solubilised into mixed micelles?
intestines
Which transporter transports cholesterol across the intestinal epithelium?
- NPC1L1 (main determinant of transport)
Which 2 transporters Two transporters can transport cholesterol back into the lumen of the intestines?
- ABC G5
- ABC G8
- – a balance between these transporters determines the net amount of cholesterol absorbed)
Where are bile acids reabsorbed?
terminal ileum
Which enzyme does cholesterol downregulate the activty of? and what does this enzyme do?
- HMG CoA reductase
- (the main enzyme to create cholesterol from acetate and mevalonic acid) at the liver –
- i.e. the amount of cholesterol synthesised in the liver is dependent on the amount of cholesterol absorbed in the small intestines
What happens to cholesterol cholesterol brought to the liver (produced IN the liver or absorbed and transported)?
- Hydroxylation by CYP7A1 enzyme, 7a-hydroxylase –> bile acids –> excreted via bile ducts
-
Esterified by ACAT –> cholesterol esters and combined with TG and apoB into VLDL (precursor to LDL)
- ACAT = Acyl-CoA: cholesterol acyltransferase
- MTP = Microsomal Triglyceride Transfer Protein (used to package cholesterol esters)
What happens to LDLs after circulation?
LDLs will bind to LDL receptor on the liver
What are HDLs responsible for?
picking up excess cholesterol from the periphery
Which transporter is important in packaging free cholesterol from the periphery into HDLs?
ABC A1
What does CETP (cholesteryl ester transfer protein) do?
mediates the movement of:
- Cholesterol from HDL to VLDL
- Triglyceride from VLDL to HDL
What does the receptor SR-B1 do?
Some of the HDLs will be taken up by the liver via SR-B1
What are the types of Hypercholesterolaemia (primary)?
- Familial hypercholesterolaemia
- Polygenic hypercholesterolaemia –
- Familial hyper-a-lipoproteinaemia
- Phytosterolaemia
Which mutations are implicated in Familial hypercholesterolaemia (FH)?
dominant mutations in:
- LDL receptor
- apoB or
- PCSK9
rarely, recessive mutations in:
- LDLRAP1
Which mutations are implicated in Polygenic hypercholesterolaemia
- NPC1L1,
- HMG-CoA Reductase,
- CYP7A1 polymorphisms
What is the cause of Familial hyper-a-lipoproteinaemia?
lots of causes, but sometimes. CETP deficiency
What is Familial hyper-a-lipoproteinaemia ?
increase in HDL
Which mutations are implicated in Phytosterolaemia?
ABC G5 & G8 mutations (in small intestine)–> premature atherosclerosis
What is the Pathophysiology of Hypercholesterolaemia (primary)?
normally:
- LDL binds to LDL-R (on coated pits of the liver)
- undergoes endocytosis
- taken to lysosome for processing and degradation
pathophysiology:
- many LDL-R mutations identified –> less LDL binds to LDL-R –> less is degraded in lysosome –> high [serum LDL]
What are the signs/symptoms seen in homzygotes with Hypercholesterolaemia (primary)?
- corneal arcus,
- atheroma of aortic root
What are the signs/symptoms seen in heterozygotes with Hypercholesterolaemia (primary)?
- corneal arcus,
- xanthomas (eye [xanthelasma], tendon)
What is the function of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)?
- bind to LDL-R and aid its degradation
*
Describe the rare cause of FH, related to a mutation in PCSK9
- autosomal dominant mutation
- gain-mutation in PCSK9 –> increased LDL-R degradation
- (–> less LDL binds to LDL-R –> less LDL is degraded –> high [serum LDL])
What are the types of Hypertriglyceridaemia (primary)?
- Familial T-I
- Familial T-IV
- Familial T-V
What is the cause of Hypertriglyceridaemia (primary) Familial T-1?
- lipoprotein lipase or apoC II deficiency
- –> Less breakdown of chylomicrons
What is the cause of Hypertriglyceridaemia (primary) Familial T-IV?
increased synthesis of Triglyceride (unknown cause)
What is the cause of Hypertriglyceridaemia (primary) Familial T-V?
apoA V deficiency
What does the picture show?
- eruptive xanthomas
- seen in primary hyperlipidaemia Familial T-I
Which particles are seen in each of the Hypertriglyceridaemia (primary) Familial types?
- Familial T-I
- Familial T-IV
- Familial T-V
- Familial T-I = chylomicrons
- Familial T-IV = vLDLs
- Familial T-V = vLDLs (with some chylomicrons)
Match each of the pictures with one of the below Hypertriglyceridaemia (primary) types:
- Familial T-I
- Familial T-IV
- Familial T-V
- Familial T-1 = left (chylomicrons in plasma)
- Familial T-IV = middle (vLDLs in EDTA blood)
- Familial T-V = right (majority vLDLs with some chylomicrons in plasma)
What is mixed hyperlipidaemia?
- high [serum LDL]
- high [serum triglyceride]
- low [serum HDL]
What are the types of Mixed hyperlipidaemia (primary)?
- Familial combined hyperlipidaemia
- Familial hepatic lipase deficiency
- Familial dys-B-lipoproteinaemia (type III hyperlipoproteinemia)
What is the cause of the Familial combined hyperlipidaemia type of primary Mixed hyperlipidaemia?
unknown cause
What is the cause of the Familial hepatic lipase deficiency type of Mixed hyperlipidaemia (primary)?
hepatic lipase deficiency
What is the cause of the Familial dys-B-lipoproteinaemia type of Mixed hyperlipidaemia (primary)?
- ApoE2 polymorphism
What are the diagnostic signs of Familial dys-B-lipoproteinaemia?
- Yellow palmar crease (LEFT),
- xanthomas on elbow (RIGHT)
What is the link between ApoE2 polymorphism and Alzheimer’s?
- ApoE2 = less Alzheimer’s (ApoE2 implicated in Familial dys-B-lipoproteinaemia)
- ApoE3 = normal
- ApoE4 = increase Alzheimer’s
What is secondary hyperlipidaemia?
non-genetic cause of increased [serum lipids]
What are some causes of secondary hyperlipidaemia?
Name some types of hypolipidaemia
- A-β-lipoproteinaemia: RARE
- Hypo-β-lipoproteinaemia
- Tangier disease: orange tonsils
- Hypo-α-lipoproteinaemia
What is A-β-lipoproteinaemia?
- hypolipidaemia disorder
- MTP deficiency (AR) –
- RARE
- –> very low LDL and vLDL
What is MTP?
- mitosomal triglyceride transfer protein
What is hypo-β-lipoproteinaemia?
- type of hypolipidaemia
- truncated apoB
- (AD)
- –> Low LDL
What is Tangier’s disease?
- Tangier disease: orange tonsils
- ABC A1 mutations
- –> HDL deficiency
What is the cause of hypo-a-lipoproteinaemia?
sometimes due to mutations of apoA-1
What is the relationship between lipids and cardiovascular disease?
- CVD is associated with serum cholesterol à deaths
- HDL = protective; LDL = deleterious
What is the pathophysiology of atherosclerosis?
Name some lipid-regulating drugs
- atorvastatin
- gemfibrozil
- ezetimibe
- colestyramine
Which lipid regulating drug is the most effective at reducing LDL?
atorvastatin
Which lipid-regulating drug is the most effective at reducing triglycerides?
Gemfibrozil
Name some novel lipid-regulating drugs
What is Lp(a) (lipoprotien A) used as a marker for?
CVD risk factor marker
How is Lp(a) used?
- Should be measured once with intermediate-high CVD/CHD risk (inc. FH)
What is a desirable Lp(a) level? What is the Tx if this is too high?
- Desirable Lp(a) = <500mg/L
- Tx is nicotinic acid 1-3g/day
What is the Tx for obesity?
- Low-calorie diet & exercise
- Iatrogenic malabsorption (Orlistat, 120-360 mg, OD)
- Bariatric surgery (BMI >40Kg/m2) – e.g. gastric banding, bypass, biliopancreatic bypass
What are the risks and benefits of bariatric surgery used to treat obesity?
- Success –> 50% loss in weight, 72% reduction of diabetes risk, reduced TG, increased HDL, reduced fatty liver, reduced HTN
- Post-op mortality = 0.1-2%
