ChemPath: Lipoprotein metabolism, CVD and obesity ✔️ Flashcards
What are the features of an atherosclerotic lesion?
- Fibrous cap
- Foam cells (macrophages full of cholesteryl ester)
- Necrotic core (full of cholesterol crystals)
Types of plasma lipoproteins:
- Chylomicrons - LARGEST
- VLDL - rich in triglycerides
- LDL - main carriers of cholesterol
- HDL
During what time will chylomicrons be most abundant?
Levels peak after eating (they are present in very small amounts in the fasted state as they have a short half-life)
Describe the uptake of cholesterol by the intestinal epithelium.
- Cholesterol entering the intestines will come from the diet and bile
- Cholesterol will be solubilised in mixed micelles
- It is then transported cross the intestinal epithelium by NPC1L1 (this is the main determinant of cholesterol transport)
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Name two transporters that transport cholesterol back into the intestinal lumen.
ABC G5
ABC G8
Where are bile acids absorbed?
Terminal ileum
What happens when cholesterol arrives at the liver?
Downregulates the activity of HMG CoA reductase
NOTE: HMG CoA reductase is responsible for the production of cholesterol from acetate and mevalonic acid
What are the two fates of cholesterol that is either produced by or transported to the liver?
- Hydroxylation by 7a-hydroxylase to produce bile acids
- Esterification by ACAT to produce cholesterol ester which is incorporated into VLDLs along with triglycerides and Apo(B)
What is the main precursor of LDL?
VLDL
LDL circulates around body for ≈3 days, then gets taken by via LDL receptor on liver
How do LDL and HDL differ in their transport?
LDL: distributing cholesterol from liver to the peripheries
HDL: taking excess cholesterol from peripheries back to the liver, using transfer protein ABCA1
Which transfer protein is important in the packaging of VLDLs?
MTP
What are the effects of CETP on the movement of substances between lipoproteins?
- Moves cholesterol from HDL → VLDL
- Moves triglycerides from VLDL → HDL
Which receptor is responsible for the uptake of some HDLs by the liver?
SR-B1
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Describe the transport and metabolism of triglycerides.
- Main source of triglycerides = from fatty food diet (absorbed in the small intestine)
- Triglycerides from fatty foods are hydrolysed to fatty acids, absorbed, and resynthesized into triglycerides which are transported by chylomicrons into the plasma
- Chylomicrons are hydrolysed by lipoprotein lipase into free fatty acids
- Some free fatty acids are taken up by the liver, and some by adipose tissue
- The liver resynthesizes fatty acids into triglycerides and packages them into VLDLs
- VLDLs are acted upon by lipoprotein lipase to liberate free fatty acids
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List the three causes of familial hypercholesterolaemia (type II).
- Caused by autosomal dominant gene mutations in:
- LDL receptor gene
- ApoB gene
- PCSK9 gene
List some mutations that are implicated in polygenic hypercholesterolaemia.
Multiple loci that lead to modest increase in cholesterol
- NPC1L1
- HMGCR
- CYP7A1
What is familial hyperalphalipoproteinaemia?
- Increase in HDL caused by deficiency of CETP
- This is associated with longevity
What is phytosterolaemia?
Photo meaning ‘plant’…
- Increased plasma concentrations of plant sterols due to mutations in ABC G5 and ABC G8 (the cholesterol transporters in the small intestine)
NOTE: this condition is associated with premature atherosclerosis as plant sterols can enter the bloodstream freely
Dsecribe the function of the LDL receptor.
- LDLs bind to LDLR in coated pits which then undergo endocytosis (thereby uptaking the LDL into the liver)
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List some clinical features of familial hypercholesterolaemia.
- Xanthelasma
- Corneal arcus
- Tendon xanthomata –> feel achilles tendon for thickness!
- Cholesterol levels extremely high (>30 mmol/L from birth)
What is PCSK9?
- A protein that binds to LDL receptors and degrades them
*NOTE: gain of function mutations result in increased breakdown of LDLR and hence increased plasma LDL levels
NOTE: loss of function mutations are associated with lower LDL levels*
List the key features of the following forms of familial hypertriglyceridaemia:
- Familial Type I
- Familial Type IV
- Familial Type V
Familial Type I:
- Caused by deficiency of lipoprotein lipase and ApoC II
- NOTE: lipoprotein lipase degrades chylomicrons and ApoC II is an activator of lipoprotein lipase
Familial Type IV:
- Characterised by increased synthesis of triglycerides
Familial Type V:
- Characterised by deficiency of ApoA V
- NOTE: these hypertriglyceridaemias show different patterns when the plasma is left overnight to separate e.g. may show chylomicrons, VLDLs etc. depending on the type of hyperlipidaemia
What is familial combined hyperlipidaemia?
Some people in the family have high cholesterol and others have high triglycerides
Unknown cause typically
What is familial dysbetalipoproteinaemia (type III)?
UNCOMMON
* Due to aberrant form of ApoE (E2/2)
* NOTE: normal form is ApoE (3/3)
* A diagnostic clinical feature of yellowing of the palmar crease (palmar striae) AND may also have irruptive xanthoma on the elbow
List some causes of secondary hyperlipidaemia.
- Pregnancy
- Exogenous sex-hormones
- Hypothyroidism
- Obesity
- Nephrotic syndrome (switches on VLDL and LDL synthesis)
List four causes of hypolipiademia and their underlying genetic defect.
Aβ-lipoproteinaemia:
- Autosomal recessive
- Extremely low levels of cholesterol
- Due to deficiency of MTP
Hypoβ-lipoproteinaemia:
- Autosomal dominant
- Low LDL
- Caused by mutations in ApoB
Tangier disease:
- Low HDL
- Caused by mutation of ABCA1
Hypoα-lipoproteinaemia:
- Sometimes caused by mutation of ApoA1
Describe the role of LDL in atherosclerosis.
- LDL becomes oxidised once it has got through the vascular endothelium
- Once oxidised it is taken up by macrophages
- Within the macrophages, the LDLs become esterified and you develop foam cells
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What can cause a thrombus?
Thin fibrous cap surrounding cholesterol –> ruptures e.g. from strain
Once cap ruptures, cholesterol is exposed, forming a thrombus
THEN, cap can either heal (progress of occlusion) OR cholesterol thrombus completely occludes the vessel
List some lipid-lowering drugs and their effect on lipid levels.
- Statins - reduce LDLs, increased HDLs, slight increased in triglycerides
- Fibrates e.g. gemfibrozil - lower triglycerides, little effects
- Ezetimibe - reduces cholesterol absorption (blocks NPC1L1)
- Colestyramine - resin that binds to bile acids and reduces their absorption
List some novel forms of lipid-lowering drugs.
- Lomitapide - MTP blocker
- REGN727 - anti-PCSK9 monoclonal antibody
- Mipomeren - anti-sense ApoB oligonucleotide
List three types of bariatric surgery.
- Gastric banding –> restricts how much people eat
- Roux-en-Y gastric bypass
- Biliopancreatic diversion
What is the definition of success in bariatric surgery?
More than 50% reduction in excess weight (excess weight = actual - ideal weight)
List some beneficial effects of bariatric surgery.
- Reduced diabetes risk
- Reduced serum triglycerides
- Increased HDLs
- Reduced fatty liver
- Reduced blood pressure