Chemical Pathology: Lipoprotein metabolism, Cardiovascular disease and Obesity Flashcards
Name the plasma lipoproteins, in order of increasing density/ decreasing size.
Chylomicrons > VLDL > LDL > HDL
Which plasma lipoprotein is predominantly associated with transport of cholesterol?
LDL (~70%)
Which plasma lipoprotein is predominantly associated with transport of triglycerides?
VLDL (~55%)
What is NPC1L1?
A transmembrane protein that transports cholesterol from the small intestine to the liver (Via lymphatics)
Outline the synthesis of cholesterol
- Occurs in the liver
- Acetate is converted to Mevalonic acid (MVA), which is converted to cholesterol (By HMG CoA reductase)
- Is down-regulated with increased absorption of cholesterol
What are ABC G5 and ABC G8?
-Transmembrane proteins involved in transport of cholesterol from liver into small intestine
How is cholesterol absorption regulated?
- NPC1L1 facilitates cholesterol absorption from small intestine into the liver.
- ABC G5 and ABC G8 transport cholesterol back into small intestine.
Outline the metabolism of cholesterol
- 2 main pathways:
1: Hydrolysed intro bile acids (by 7-α-hydroxylase)
2: Esterified into cholesterol esters (By ACAT) - Encorporated into VLDL (along with apoB and triglycerides)
- MTP transfers VLDL from liver into plasma.
- VLDL can be converted into LDL which is taken up by cells with LDL receptors (Mainly peripheries)
What is the function of MTP?
- Microsomal Triglyceride transfer Protein
- Transports newly formed VLDL from liver into plasma
What is the function of apoB?
- Apolipoprotein B
- The main protein constituent of lipoproteins
- Encorporated into VLDL with cholesterol and triglycerides
What is the function of ACAT?
- Sterol O-acyltransferase
- Converts cholesterol into cholesterol esters.
What is the main function of LDL?
-Transports cholesterol from the liver to the peripheries, where it is taken up by cells with LDL receptors.
/////////////////////////////////////////////
(ie transports cholesterol to peripheries)
What is the main function of HDL?
-Picks up excess cholesterol from the peripheries into the liver.
What is the function of ABC A1?
-ABC A1 mediates the movement of free cholesterol from peripheral cells to HDL
What is the function of CETP?
- Cholesterol Ester Transfer Protein
- Mediates the movement of cholesterol esters from HDL into VLDL, and the movement of triglycerides from VLDL to HDL
What is the function of SR-B1?
-Absorbs HDL from the plasma into the liver
Describe how cholesterol crystals form in atherosclerosis
- Excess LDL is oxidised and taken up by macrophages
- Cholesterol is esterified, leading to formation of foam cells.
- Foam cells die, releasing cholesterol
- Cholesterol crystals form in necrotic core
Outline triglyceride transport and metabolism
- Absorbed in the small intestine, chylomicrons are formed in the plasma
- Chylomicrons are hydrolysed (By LPL: Lipoproteinlipase, in capillaries) into free fatty acids
- Fatty acids are taken up by the liver and adipose tissue.
- Liver resynthesises triglycerides from fatty acids
- Triglycerides are exported by VLDL
- Triglycerides cyclically hydrolysed into free fatty acids by LPL.
Clinical features of familial hypercholesterolaemia?
- Xanthalasma: Eye lumps
- Homozygous: high cholesterol in childhood. Arcus of cholesterol around the iris of the eye.
- Heterozygous: High cholesterol in early adulthood
- High cholesterol on bloods, of course
- Xanthoma: lump on back of achilles tendon
- Eruptive xanthoma: red papules
Outline the causes of hyperlipidaemia
- Primary hypercholesterolaemia: eg familial, LDL receptor mutation.
- Primary hypertriglyceridaemia: eg familial type I, lipoprotein lipase deficiency.
- Primary mixed hyperlipidaemia: eg familial, dys-β-lipoproteinaemia (type III). ApoE polymorphism: yellow palmer crease.
- Secondary hyperlipidaemia: eg hypothyroidism
Oultine the causes of hypolipidaemia
- A-β-lipoproteinaemia: MTP deficiency (Microsomal triglyceride transfer protein)(recessive).
- Hypo-β-lipoproteinaemia: truncated apoB (dominant)
- Tangier disease: ABC A1 mutation leading to HDL deficiency.
Describe the relationship between lipids and cardiovascular disease
- Raised serum cholesterol is associated with increased incidence of cardiovascular disease.
- Increased LDL is also associated
- Decreased HDL is also associated
Describe current lipid-lowering therapy
- Statins (eg atorvastatin) are mainstay treatment. Reduces LDL by up to 50%. Reduce CVD mortality.
- Gemfibrozil: reduces triglycerides
- Ezetimibe: cholesterol absorption blocker (inhibits NPC1L1) -
- Colestyramine: binds bile acids, preventing reabsorption.
Outline the treatment for obesity
- Hypocaloric diet and excercise
- Orlistat: prevents absorption of fat
- Bariatric surgery: if BMI >40 (eg gastric band)
Outline the causes of Secondary hyperlipidaemia
- Hormonal: Pregnancy, exogenous hormones, hypothyroidism
- Metabolic: Diabetes, gout, obesity
- Renal dysfunction: Nephrotic syndrome, CKD
- Obstructive liver disease
- Toxins: eg alcohol.
- Iatrogenic: eg antihypertensives
Give one cause of primary hypercholesterolaemia
-Familial, LDL receptor mutation.
Give one cause of primary hypertriglyceridaemia
-Familial type I, lipoprotein lipase deficiency.
Give one cause of primary mixed hyperlipidaemia
-Familial, dys-β-lipoproteinaemia (type III). ApoE polymorphism: yellow palmer crease.
