Lipids and atherosclerosis
Lipid metabolism and atherosclerosis
Adiposity result from positive energy balance: more energy intake (fook
intake) than energy expenditure (thermogenesis, exercise and rest
metabolism) First store extra energy in white adipocytes when
capacity is research then fat accumulates in fat cells between organs.
When fat cells expand more they can die and attract macrophages this lead to insulin
(convert glucose to glycogen) resistance whereby adipose tissue leaks lipids and
these are going to the liver and other organs (=lipid overflow)
Liver: liver doesn’t respond to insulin anymore and start to produce lipids
Muscle: muscles uses less lipids this lead to increase in lipid in the plasma
This lead to dyslipidemia (abnormal amount of lipids in the blood) which is a risk
factor for atherosclerosis and cardiovascular disease
Macronutrients provide the body with energy:
1. Proteins; building muscles
2. Carbohydrates (sugars); energy comes from this
3. Lipids (fat)
a. Triglycerides (glycerol + 3 fatty acids); storage form of fatty acids
Fatty acids are transported from the intestine to other organs via the
blood:
- Heart: FA are beta-oxidized this lead to ATP production and
CO2
- Muscle: FA are beta-oxidized this lead to ATP production and
CO2
- White adipose tissue (WAT): FA are taken up but become
again triglycerides (storage!)
- Brown adipose tissue (BAT): FA are taken up and burned into
heat and CO2
Lot of brown fat in neonates because need lot of heat
b. Cholesterol (not a fat but a sterol); lot in animal-rich diet, hydrophobic
Need it because
- Component of cell membranes
- Precursor of bile (gal) acids; emulgate and absorb lipids from
the gut
- Precursor of vitamin D and steroid hormones
Cholesterol is transported from the intestine to other organs via the
blood
- Testes: androgen (e.g. testosterone) production
- Ovaries: estrogen (e.g. estradiol) production
- Adrenals: mineralo- and glucocorticoids (aldosterone, cortisol)
Female (1600-2000 kcal/day) need less macronutrients compared to male (2200-
2800 kcal/day) because less muscles and these use a lot of energy
Lipoproteins transport triglycerides and cholesteryl esters trough the
blood:
In the core: triglycerides (TG) and cholesteryl esters (CE)
Shell: monolayer of phospholipids (PL)
o Hydrophilic on the outside
Cholesterol embedded
, Apolipoproteins on the shell
4 types of lipoproteins:
1. HDL: high density lipoproteins – lot of cholesterol – less triglycerides – apoA1
(good cholesterol – transport cholesterol tissue to liver)
2. LDL: low density lipoproteins – apoB100 (bad cholesterol – transport
cholesterol liver to tissue)
3. VLDL: very low-density lipoproteins – apoB100
4. Chylomicron – less cholesterol – lot of triglycerides – apoB48
After eating – exogenous pathway
Triglycerides are absorbed into the gut by transporters or by passive
absorption
Cholesterol is taken up in the gut by NPC1L1 (Niemann-Pick C1-like
1)
TG, CE and PL are re-synthesized in SER
apoB48 is produced in RER
By the action of MTP (microsomal triglyceride transfer
protein) lipid droplets are fused with apoB48 which leads to
precursors of chylomicrons. Chylomicrons go into the
lymphatics and from here it enters the blood stream
Main function of chylomicrons is to deliver fatty acids towards
organs (heart, muscle, WAT, BAT – WAT takes up the most FA) by
interaction with LPL (lipoprotein lipase) which is present in all of
these tissues. By interaction with LPL FA are generated from TG
and taken up by these tissues.
Modulators of lipoprotein lipase (LPL):
ApoC2: obligatory coactivator
ApoA5: stimulator
ApoC1: inhibitor
ApoC3: inhibitor
After this action decreased TG content, decreased particle size and
they have accepted apoE.
Most apoE is not produced by intestine but taken up in the circulation.
ApoE is required to bind the particles to hepatocytes (cells in the liver). The
capillaries in the liver are fenestrated, the chylomicrons are too big to pass this
endothelium. So, the have to be reduced in size to pass this fenestrated endothelium
layer and then they come in contact with hepatocyte.
2 receptors in liver who are involved in endocytosis of the particle:
1. LDLr (LDL receptor); smaller particles more affinity for
LDLr
LDLr bind chylomicron remnants invaginated into
clathrin-coated pit endosome formation uncoupling
department where LDLr is recycled back to surface and
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