Lipoprotein and Cholesterol Metabolism Flashcards
problems with lack of fat digestion using fat substitutes or lipase inhibitors
= insufficient production of bile salts or pancreatic lipase deficiency, can lead to malabsorption of fats and fat-soluble vitamins.
This can result in symptoms such as steatorrhea (excess fat in the stool), nutrient deficiencies, and gastrointestinal discomfort.
Use of fat substitutes or lipase inhibitors can also affect fat digestion. Fat substitutes like Olestra which are not attacked by lipases may cause gastrointestinal side effects, while lipase inhibitors such as Orlistat can reduce fat absorption, potentially leading to steatorrhea and nutrient deficiencies if not used appropriately.
fat digestion overview
fat is hydrophobic
–> needs to be made into an emulsion for digestion
digestion begins in the small intestines after it is absorbed = where the fat needs to be carried around the bloodstream in capsules called lipoproteins
- bile salts mix with dietary fat which forms chyme and creates an emulsion
- bile saltsare needed emulsify large fat droplets (dietary fat) into smaller droplets called micelles (increasing SA for pancreatic lipase) in the small intestine
- pancreatic lipase : produced by the pancreas to break down triglycerides into FAs and glycerol (plus other mono- and di-acyl glycerols)
- Once broken down into fatty acids and glycerol, these smaller molecules are to be absorbed by intestinal cells (by the cells lining the small intestine.)
- Once absorbed, the fatty acids and glycerol are transported to various tissues throughout the body and then form together into triglycerides inside the tissuesthrough a process called esterification.
- Triglycerides are transported through the bloodstream in lipoprotein particles, such as chylomicrons and VLDL, to various tissues where they are either stored or used for energy.
Pancreatic Lipase
key enzyme involved in the digestion of fat in the small intestine.
It acts on the emulsified fat droplets
–> it hydrolyses triglycerides into fatty acids and glyercols (Plus, a mixture of mono- and di-acyl glycerols)
Pancreatic lipase requires the presence of bile salts for optimal activity (bile salts break down large fat droplets into smaller ones which increases SA for enzyme action)
bile salts
Cholesterol is a precursor molecule for bile salt synthesis, and the liver converts cholesterol into bile salts
Polar groups are added on cholesterol
Made in the liver, Stored in the gall bladder and when fat is ingested, bile salts are secreted towards small intestine
==> mixes together with fat that comes from diet
After digestion of fat, bile salts are reabsorbed and taken back to the liver Via hepatic portal vein
Some bile salts that are not reabsorbed are excreted in the faeces : the way in which cholesterol is metabolised and
disposed
Bile salts are amphipathic/amphiphilic molecules that have both hydrophilic and hydrophobic regions, allowing them to interact with both water and fat molecules. This property helps in the emulsification of fats, breaking them down into smaller droplets.
Describe the general features of lipoproteins
Lipoproteins are complex particles composed of lipids (triglycerides, cholesterol, phospholipids) and proteins (apolipoproteins).
interior package is very hydrophobic
the outer layer is made of a phospholipid monolayer
apoproteins attached (are used for target cells to identify)
package contains triglycerides & cholesterol
they transport lipids through the bloodstream, as lipids are insoluble in water and need to be packaged in lipoprotein particles for transport.
Types of lipoproteins :
* chylomicrons
* very-low-density lipoproteins (VLDL)
* low-density lipoproteins (LDL)
* high-density lipoproteins (HDL).
lipoproteins pathway from gut
triglycerides are formed and packaged into the lipoprotein, chylomicrons
–> very very low density, contains fat and cholesterol
enters the lymphatic system and travels through lymphatic system and circulation to tissues
the packaging of cholesterol in lipoproteins
cholesteryl esters are inside the lipoproteins (undergo esterification)
free (unesterified) cholesterol is on the outer layer of lipoprotein
cholesterol has one end which is polar, which makes it hydrophilic, (the centre is very hydrophobic), need to esterify it to have it in the inner package
esterification:
* joins a fatty acid on the polar end of the cholesterol molecule
* cholesterol = cholesteryl ester
* makes it very hydrophobic, perfect for core of lipoprotein
chylomicrons in blood
chylomicrons in the blood, travelling to deliver fats to target cells
target cells express the lipoprotein lipase (LPL) receptors on cell surface in capillaries to interact with chylomicron
lipoprotein particles carrying triglycerides bind to the cell surface via LPL receptors => lipoprotein lipase (LDL ) anchored on the cell surface becomes activated
LPL then acts on the triglycerides within the lipoprotein particles, breaking them down into fatty acids and glycerol, which can then be taken up and utilized by the target cells for energy production or storage.
cells can eat up the fat = as in fat is hydrolysed and fatty acids and glyercol is taken up to be used for oxidation or storage
LPL receptors expression in tissues are stimulated by insulin
Remember : G-3P is needed to store fatty acids in the cell, can steal it from glycolysis
chylomicrons remnants + liver
after cells have taken up some free fatty acids from the chylomicrons that were released from the small intestine = leaves behind chylomicron remnants
chylomicron remnants are transported to the liver, and actively endocytosed
==> remnants are chopped up and liver adds any fat produced by the body
–> reassembles them and packaged up into VLDL
–> VLDL secreted into the bloodstream and exported from the liver
VLDL
contains cholesterol and triglycerides
similar to chylomicrons, will circle in the blood stream and visit tissues, any tissues that want fats from VLDL will express LPL receptors to eat up the fats
== eat up enough fats they produce IDL (VLDL remnants) or straigh into LDLs
since triglyercides were eaten up by tissues, LDLs are proprtionally higher in cholesterol to fatty acid
LDL
produced from VLDL - endocytosed by liver
function : since its proportionally higher in cholesterol, it delivers it to tissues that want cholesterol
target tissue cells express LDL receptor (instead of LPL) to signal for LDL particles to bind
–> gets endocytosed by cell and mash it up to get the fatty acids and esp. cholesterol from it
excess LDL get back to liver and repackaged again and sent out again with the liver’s own cholesterol and fat that has been synthesised
the endogenous formation of cholesterol and identify the rate limiting step
HMG-CoA reductase is the rate limiting step
the very first step, where the enzyme converts acetate into mevalonate
the enzyme’s substrate is acetate/acetyl CoA
it joins acetate units together = forming product that contains part of molecule called isoprene which will fold to form rings in cholesterol
Nearly all of our cells can make cholesterol themselves
the rate limiting step and inhibition of the process of endogenous cholesterol formation
HMG-CoA reductase is what we target to lower cholesterol, catalyses the first step in producing cholesterol
–> highlyyyy regulated by insulin and feedback inhibition by own product; gene expression and rate at which the enzyme turnsover itself, even circadian rhyth
also inhibited by statins, switch the enzyme off in all cells and tissues to prevent cholesterol synthesis
==> tissues express LDL receptors, take cholesterol from LDL and lower cholesterol in our body and lower circulating LDL in blood
why LDL is bad
high levels of LDL cholesterol are associated with increased risk of atherosclerosis and cardiovascular disease.
==> LDL particles can deposit cholesterol in arterial walls, leading to plaque formation and narrowing of blood vessels esp. coronary arteries or in the brain
- LDL get oxidised easily (since the bloodstream is filled with RBC carrying O2, so highly oxidative enviro) = oxidated LDLs
- macrophages come and start phagocytosing these LDLs until they are filled with LDLs and are now called foam cells
- foam cells then signal to other immune cells to cause an inflammation
- ==> contributes to the buildup of plaque
why is HDL good
HDLs are patrolling in the bloodstream (from the liver and intestine)
it picks up any excess cholesterol from cells and transports it back into the liver
liver repackages cholesterol for either re-export or bile salt synthesis (in a more appropriate form)
HDLs are much smaller, higher in protein, lower in fats
–> This process, known as reverse cholesterol transport, helps prevent the buildup of cholesterol within arterial plaques.
