Lipid Transport Flashcards
Where are lipids transported from?
- gut to liver
- liver to non-hepatic tissue including adipocytes
- non-hepatic tissue back to liver
Fats + lipids in circulation?
Triacylglycerols (45%) Cholesterol esters Cholesterol (15%) Phospholipids (35%) Free FA (5%) % in plasma varies with nutritional state All are insoluble in water
How polyunsaturated FA are ligands for transcription factors involved in energy metabolism?
Role in regulation of insulin metabolism :
increase lipid oxidation in liver + muscle
decrease genes involved in lipogenesis in liver + adipose tissue
-Increase expression of UCP-2 + 3 in mitochondria to increase thermogenesis
Features of FFA?
- Formed from triacylglycerides stored in adipose tissue
- Circulates bound to protein as Na+ particularly albumin as unbound FA acts as a detergent
- Saturation occurs at about 2mM FA molecules
- FA enter cells by simple diffusion
- Intracellular concentration FFA kept low
Features of lipoprotein?
-Carried in blood as plasma lipoproteins
-5 types of lipoprotein :
chylomicrons
very low density lipoproteins (VLDL)
intermediate density lipoprotein (IDL)
low density lipoproteins (LDL)
high density lipoproteins (HDL)
-Each particle has diff function
Functions of apolipoproteins / apoproteins?
-Structural = form substrate in which lipid can be constructed
-Solubilise lipids = so body transports a difficult class of
molecules
-Act as enzymes or enzyme cofactors (co-enzymes) :
Apo C2 activates lipoprotein lipase
ApoA1 for lecithin:cholesterol acyltransferase
-Tissue targeting :
Apo B100 + Apo E binds LDL receptor
Apo E binds HDL receptor
Lipoprotein composition?
Chylomicrons : B48, Apo C2, C3, E VLDL : B100 Apo C1, C2, C3, E (VLDL made in liver released with only B100 when circulates it gets Apo C + E from HDL) IDL : B100, Apo E LDL : B100 HDL : Apo A1, A2, C1, C3, D, E
Describe how dietary lipids travel?
- in gut triglycerides -> FA + monoacylglycerols via lipases
- pass from gut lumen into gut epithelial cells
- converted back into triglycerides
- triglycerides assembled into chylomicron with other lipids (phospholipids, cholesterol) + proteins.
- chylomicrons released into lymphatics
- carried via thoracic duct to SVC
- so dietary fats avoid direct delivery to liver + made available to extrahepatic tissue (diff to digested proteins, carbs which released into portal vein, delivered directly to liver
Features of dietary lipids?
- Low density due to high TG
- Apo C2, C3, E, B48 added in SER
- Secreted by reverse pinocytosis in to lymphatics
Features of chylomicron?
- Content reflects meal composition
- Low density due to TAG
- Contain fat-soluble vitamins A + E
Describe circulation of chylomicron
-circulate for 1hr but half-life of TAG only 5min
-so modified by lipoprotein lipases in circulation
-breaksdown TAG –> uptake of FA by tissues
-in circulation density increases as TAG removed - chylomicron remnants
-removed by liver by interaction of Apo E with
receptors on hepatocytes
Role of vit E?
antioxidant preventing oxidation of lipids which are associated with heart disease
Describe how lipoprotein lipase (LPL) works
- expressed on top of endothelial cells
- binds to + activated by Apo C2 on lipoprotein
- TG broken down + diffusion across membrane of FFA across membrane
- continues as chylomicron circulates
- gains density
What’s LPL on adipocytes stimulated by?
insulin
Diff types of hyperlipidaemia?
- Type 1: Def in lipoprotein lipase or Apo C2 + characterised by high plasma triglyceride
- Type 2: Genetic defect in synthesis, processing or function of LDL receptor + characterised by high LDL
- Type 4: Most common form –> raised VLDL conc due to obesity or alcohol abuse
Role of VLDL
transport lipids derived from liver around body
Role of chylomicrons?
transporting exogenous lipids from gut around circulation
What are VLDLs?
-synthesised in liver ER + golgi
-released with B100 + acquire Apo E, C2 from HDL
-interact with endothelial layer + metabolised by LPL
-remnant removed by liver by apoE (TG half life 15-60 min) :
60% VLDL remnants removed by liver
40% removed by adrenal + gonadal tissue (cholesterol used for hormone production) using B100 to bind to LDL
If excess LDL, receptors saturated + excess removed via low affinity scavenger receptor
What are VLDLs formation enhanced by?
- Excess dietary carb
- Circulating FFA
- Alcohol enhances VLDL synthesis so increases lipid transport
- Insulin + decreased glucagon
Describe process of VLDL
-VLDL released as nascent particle
-acquires ApoE + ApoC-2 from HDLs
-form mature VLDLs
-circulate + acted upon by LPL
-FA enters tissues + get smaller
-2 pathways :
~return to liver as VLDL remnants – removed by ApoE (50%)
~converted into IDLs via removal of more TGs
in liver sinusoids IDLs -> LDLs
LDLs taken up by liver + removed or taken up by non-hepatic tissue via interacting with LDL receptor
Role of LDL?
carrier of cholesterol
What are LDLs?
- Metabolised slowly 3 days
- Carry cholesterol to periphery + regulate de novo synthesis of cholesterol via B100 binding to specific receptor on hepatocyte
Role of HDL?
reverse cholesterol transport
- take up circulating cholesterol from VLDLs, dead, dying cells
- take cholesterol back to liver + steroid producing cells
How are HDLs made?
in liver + intestine by budding from VLDL + chylomicrons
from free ApoA1
Sig of receptor-mediated endocytosis?
- Lipoproteins removed from circulation by receptor-mediated endocytosis
- Lipoproteins act at specific tissues via receptor-mediated endocytosis
Features of HDLs?
- Circulating reservoir of apolipoproteins (C2 + ApoE)
- Contain lectin cholesterol acetyltransferase (LCAT) which esterifies cholesterol
- HDL binds to lipoproteins + cells via ApoE - vital for cholesterol transfer
Good vs bad cholesterol?
HDL is good cholesterol
LDL is bad cholesterol
HDL/LDL ratio assesses susceptibility to heart disease
Normal ratio is 3.5
Describe uptake of LDLs?
- LDLs in circulation bind to specific receptors expressed on endothelial cells
- receptor + LDL is endocytosed
- vesicle fuses with endosomes
- endosomes contain enzymes for breakdown of protein + metabolism of lipids
- receptor goes off + re-inserted into membrane
- further fusion with lysosome so more hydrolytic enzymes
- receptor + apoliprotein broken down
- forming AA, phospholipids, FFA, triglycerides to give lipids
- cholesterol esters stored + utilised
What regulates cholesterol uptake + synthesis?
Amount of cholesterol in the cell itself by amount that it uptakes + amount cell is making itself :
- ↓ cholesterol = more LDL receptor expressed
- ↑ cholesterol = inhibits HMG-CoA reductase (rate-limiting step in cholesterol synthesis) - target for therapy
What effect does an increase in HMG-CoA reductase have on expression of LDL receptors?
-synthesis of LDL receptor + expression negatively regulated by intracellular conc of cholesterol
-↓ intracellular conc of cholesterol –> less cholesterol synthesis from ACoA so LDL receptor increase (HMG-CoA reductase is rate limiting step in cholesterol synthesis
Describe effect of statins on cholesterol
- inhibit HMG-CoA reductase (as it’s a competitive inhibitor: same Vmax but Km increased)
- decrease cholesterol synthesis within cells
- increase in synthesis + expression of LDL receptor
- increase LDL-cholesterol uptake
- lower circulating cholesterol
Features of scavenger receptor?
- Present on endothelial cells, macrophages, VSMC
- Low affinity active when plasma LDL high or oxidised
- Not regulated by cholesterol
Role of Apo100?
present on VLDL and LDLs + bind to LDL receptor for uptake
Role of ApoE?
present on VLDL, HDL, chylomicrons + allow removal from circulation (by specific tissues)
Where’s LDL receptor present?
VLDL, LDL
Where’s LDL-like receptor present?
VLDL, LDL, chylomicron
Where’s scavenger receptor present?
LDL
Affinity of LDL receptor?
high
Affinity of LDL-like receptor?
high
Affinity of scavenger receptor?
low
What does LDL receptor bind to?
ApoB100
What does LDL-like receptor bind to?
ApoE
What’s LDL receptor regulated by?
cholesterol
What’s LDL-like receptor regulated by?
cholesterol
What’s scavenger receptor regulated by?
unregulated
Tissue distribution of LDL receptor?
liver
Tissue distribution of LDL-like receptor?
liver
Tissue distribution of scavenger receptor?
endothelial cells, macrophages
Loss of LDL receptor function?
- Familial Hypercholesterolemia (FH)
- Homozygous individuals:
1. High serum cholesterol (800mg/ml, normal is 200mg/ml)
2. Atherosclerosis
3. Die young from heart attacks
4. De novo synthesis is not regulated by LDL (as cell thinks it has less cholesterol) - Single AA substitution prevents localisation of LDL receptor to coated pits
Role of scavenger receptors?
take up LDL from plasma when elevated but only active when circulating levels of plasma LDL very high
Regulation of lipoprotein?
-Hormonal regulation : insulin, cortisol, thyroid hormones
-Nutritional status :
decreased synthesis during fasting
increased by dietary fats – unsaturated fats
-LDL expression : oestrogen
Abnormalities of lipid transport?
-DM :
increased FFA mobilisation
decreased chylomicron + VLDL utilisation
-Gene defects : apolipoproteins, enzymes or receptors leading to hypercholesterolaemia, atherosclerosis
-Obesity : hypertension, NIDDM, hyperlipidaemia, hyperglycaemia
