ChemPath: Lipoprotein metabolism, CVD and obesity Flashcards
What are the features of an atherosclerotic lesion?
- Fibrous cap
- Foam cells (macrophages full of cholesteryl ester/ox-LDL)
- 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)
Name two transports that transport cholesterol back into the intestinal lumen.
ABC G5
ABC G8
Transports back to lumen, promoting elimination
(opposite action of NPC1L1)
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 triglycerids and ApoB
Which transfer protein is important in the packaging of VLDLs?
MTP (Microsomal triglyceride transfer protein)
*lomitapide is an MTP inhibitor
*Packaging HDLs -> ABCA1
Packaging LDLs -> MTP
Which transfer protein is important in the packaging of HDLs?
ABCA1
*Packaging HDLs -> ABCA1
Packaging LDLs -> MTP
Packaging HDLs -> ABCA1
Packaging LDLs -> MTP
What are the effects of CETP on the movement of substances between lipoproteins?
- Moves cholesterol from HDL → VLDL
- Moves triglycerids 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 are hydrolysed into FFAs + glycerol (by the action of lipoprotein lipase), absorbed, then resynthesized into triglycerides
- Transported in the plasma by: chylomicrons & VLDLs
- Some FFAs are taken up by the liver, and some by adipose tissue
- The liver resynthesizes fatty acids into triglycerides and packages them into VLDLs to be transported
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
Meaning prevention of transporting cholesterol into intestinal lumen for elimination
Hence 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
- Atherosclerosis affecting coronary arteries and root of aorta
- In some cases, death <20 years
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
List the key features of the following forms of primary hypertriglyceridaemia:
- Familial Type I
- Familial Type IV
- Familial Type V
Familial Type I:
- Caused by deficiency of lipoprotein lipase (hence can’t hydrolyse TGs) 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
What is familial combined hyperlipidaemia?
Some people in the family have high cholesterol and others have high triglycerides
What is familial dysbetalipoproteinaemia (type III)?
- Polymorphism of ApoE
- Specifically, due to aberrant form of ApoE (E2/2) (normal form is ApoE (3/3))
- A diagnostic clinical feature of yellowing of the palmar crease (palmar striae)
List some causes of secondary hyperlipidaemia.
- Pregnancy
- Hypothyroidism
- Obesity
- 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
Hypoα-lipoproteinaemia:
- Sometimes caused by mutation of ApoA1
Hypoβ-lipoproteinaemia:
- Autosomal dominant
- Low LDL
- Caused by mutations in ApoB
Tangier disease:
- Low HDL
- Caused by mutation of ABCA1
Describe the role of LDL in atherosclerosis.
- LDL becomes oxidised once it has got through the vascular endothelium = oxLDL
- oxLDL gets esterified & phagocytosed by macrophages, becoming foam cells
List some lipid-lowering drugs and their effect on lipid levels (4).
- Statins - ↓ LDLs, ↑ HDLs, slight increased in triglycerides
-
Nicotinic acid - lipoprotein(a) levels, ↑HDL, ↓TG, ↓LDL
Ezetimibe - inhibits NPC1L1 receptor, thus inhibiting cholesterol uptake in SI - Colestyramine - resin that binds to bile acids and reduces their absorption
List some novel forms of lipid-lowering drugs.
- Lomitapide - MTP blocker
- REGN727 (evolucumab, alirocumab) - anti-PCSK9 monoclonal antibody
- Mipomeren - anti-sense ApoB oligonucleotide
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
List some beneficial effects of bariatric surgery.
- Reduced diabetes risk
- Reduced serum triglycerides
- Increased HDLs
- Reduced fatty liver
- Reduced blood pressure
Indications for bariatric surgery
Indicated if BMI >40, or >35 + comorbidity
Outline management for obesity
Conservative (diet + wt loss)
Medical: orlistat
- profound flatulence & diarrhoea, so poor adherence
Surgical: bariatric surgery
- 3 types - gastric sleeve, roux en y, biliopancreatic diversion
What is rimonabant, why was it discontinued
Medical tx for obesity
Cannabinoid antagonist
Discont due to inc risk of suicide
Rate-limiting step in cholesterol synthesis, also a target for statins?
HMG CoA reductase
Function of lipoproteins?
Carry triglycerides and cholesterol
Name the lipoproteins, in order of lowest to highest density
Chylomicron (high triglyceride content, and high after eating)
VLDL
LDL
IDL
HDL
