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)
What is the biggest plasma lipoprotein?
Chylomicrons
During what time will chylomicrons be most abundant?
After eating (they are present in very small amounts in the fasted state)
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)
- balance between NPC1L1 and ABC G5,G8 determines amount of cholesterol absorbed
Name two transports 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
If more cholesterol absorbed in SI, less will be made by liver
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 triglycerids and ApoB
VLDL is precursor for LDL
Which transfer protein is important in the packaging of VLDLs?
MTP
Which transfer protein is important in the packaging of HDLs?
ABCA1
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
Describe the transport and metabolism of triglycerides.
- 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
List the three causes of familial hypercholesterolaemia (type II).
- Caused by autosomal dominant gene mutations in:
- LDL receptor
- ApoB
- PCSK9
List some mutations that are implicated in polygenic hypercholesterolaemia.
- NPC1L1
- HMGCR
- CYP7A1
What is familial hyperalphalipoproteinaemia?
- Increase in HDL caused by deficiency of CETP
- This is associated with longevity
What is phytosterolaemia?
- Increased plasma concentrations of plant sterols due to mutations in ABC G5 and ABC G8
NOTE: this condition is associated with premature atherosclerosis
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)
List some clinical features of familial hypercholesterolaemia.
- Xanthelasma
- Corneal arcus
- Tendon xanthomata
Heterozygous is much more common for FH than homozygous
What is PCSK9?
- A protein that binds to LDL receptors (especially on liver) and degrades them
NOTE:
gain of function mutations result in increased breakdown of LDLR and hence increased plasma LDL levels –> Rare cause of FH
loss of function mutation cause decreased plasma 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:
- decreased clearance of chylomicrons
- Caused by deficiency of lipoprotein lipase and ApoC II
- NOTE: lipoprotein lipase degrades chylomicrons and ApoC II is an activator of lipoprotein lipase
high chylomicrons
Familial Type IV:
- Characterised by increased synthesis of triglycerides
high VLDL
Familial Type V:
- Characterised by deficiency of ApoA V
high chylomicrons + VLDL
- NOTE: these hypertriglyceridaemias show different patterns when the plasma is left overnight to separate
What is familial combined hyperlipidaemia?
Some people in the family have high cholesterol and others have high triglycerides
What is familial dysbetalipoproteinaemia (type III)?
- Due to aberrant form of ApoE (E2/2)
- NOTE: normal form is ApoE (E3/3)
- A diagnostic clinical feature of yellowing of the palmar crease (palmar striae) + eruptive xanthoma on elbow
List some causes of secondary hyperlipidaemia.
- Pregnancy
- Hypothyroidism
- Obesity
- Alcohol
- Diabetes
- Nephrotic syndrome
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
List some lipid-lowering drugs and their effect on lipid levels.
- Statins - reduce LDLs, increased HDLs, slight increased in triglycerides
- Fibrates - lower triglycerides, little effect on HDL + LDL
- Ezetimibe - reduces cholesterol absorption (blocks NPC1L1) –> reduce LDL
- Colestyramine - resin that binds to bile acids and reduces their absorption (so liver makes more bile acid from cholesterol) –> reduce LDL
List three types of bariatric surgery.
- Gastric banding
- Roux-en-Y gastric bypass
- Biliopancreatic diversion
What is the definition of success in bariatric surgery?
More than 50% reduction in excess weight
Obesity treatment
low calorie diet
+ exercise
Orlistat –> inhibits pancreatic lipase
Bariatric surgery –> if BMI >=40
List some beneficial effects of bariatric surgery.
- Reduced diabetes risk
- Reduced serum triglycerides
- Increased HDLs
- Reduced fatty liver
- Reduced blood pressure
What are the types of lipoprotein
Chylomicron - largest
Very-low density Lipoprotein
Low-density lipoprotein
High density lipoprotein - smallest
What do the different lipoproteins mainly carry
Chlomicrons - <5% triglycerides
VLDL - 55% triglycerides
LDL - ‘bad’ cholesterol + 29% triglycerides
HDL - ‘good’ cholesterol + 11% of triglycerides
Note: chylomicrons have short half life in plasma
Role of HDL
carry cholesterol from periphery to liver
Role of LDL
Carry cholesterol from liver to periphery
delivers to cells with LDL receptors
Causes of primary hypercholesterolaemia
Familial hypercholesterolaemia
Polygenic hypercholesterolaemia
Familial hyperalphalipoproteinaemia
Phytosterolaemia
