24 - Lipid Utilization and Transport Flashcards
What is a monolayer?
A layer of phospholipids that spontaneously forms on the surface of an aqueous solution
What is a bilayer vesicle?
A vesicle made of a double layer of phospholipids, spontaneously made in aqueous solution
What is a lysophospholipid?
Any derivative of a phospholipid in which one or both acyl derivatives have been removed by hydrolysis (eg. only have one chain descending form headgroup)
Where are pilant chain segments found? Stiff chain segments?
They are the ends of hydrophobic side chains of fatty acids in cell membrane lipid bilayers.
Stiff chain segments are the segments of the side chains that are next to the polar hydrophilic headgroups and the pilant chain segments
Eg. (In a membrane)
- Polar hydrophilic headgroups 1
- Stiff chain segments (hydrophobic chain 1)
- Pilant Chain segments (hydrophobic chain 1)
- Pilant chain segments (hydrphobic chain 2)
- Stiff chain segments (hydrophobic chain 2)
- Polar hydrophilic headgroups 2
What do scramblases do?
They are energy-independent, can flip-flop phospholipids across a membrane
What do flippases do?
Flippases (otherwise known as phospholipid translocases) can can flip-flop phospholipids in one direction using ATP (they are ATPases)
What are two ways that phospholipids in membranes can move spontaneously and one way that they can move with facilitation?
Spontaneously
- Lateral diffusion
- Rotation
With Help
- Flip-flop
Cell membranes must be fluid at body temperatures. How do they achieve this through fatty acid composition?
Be creating the right balance of fatty acids with more double bonds to create less tighter packing and greater fluidity.
This is also in response to temperature, which can affect the fluidity of the membrane (around a transition temperature)
What keeps lipid membranes fluid over broad ranges of temperature to increase membrane stability? How?
Cholesterol. When it intercalates it creates looser packaging of lipids in the membrane.
What is cholesterol? What type of ring system does it have?
A steroid with a hydrophobic, planar ring system. It has a hydrophilic hydroxyl group and a hydrophobic side chain.
What two things does cholesterol most strongly interact with?
Sphingolipids
Saturated side chains (with rigid structure)
What are integral membrane proteins? What do they require?
Proteins embedded in the membrane. Must have hydrophobic stretches (transmembrane domains)
What are peripheral membrane proteins?
Associated with membrane through non-covalent interactions which integral proteins or through a covalently linked hydrophobic side chain (eg. a fatty acid)
What part of a membrane can connect extracellular and intracellular sides?
Transmembrane proteins
What are lateral microdomains in lipid membrains?
Lipid rafts. They are membrane domains of more rigid structure, often with cholesterol and sphingolipids. They are very tiny (nanoscale) and transient (rapid assembly and disassembly).
They can serve to cluster proteins so that they can interact int the membrane
What cannot cross the cell membrane by simple diffusion? (2)
Hydrophilic molecules
Ions
What two things serve to regulate compartmentation at membranes?
Transporters and channels
What is facilitated diffusion?
A channel that allows molecules to diffuse across a membrane
What is secondary active transport?
Where molecules are diffused across a membrane in exchange for another molecule being diffused in the other direction.
What is primary active transport?
Where a transporter uses the hydrolysis of ATP to generate energy to pump a molecule across a membrane
What is passive transport?
Transport down the concentration gradient, from the side of higher concentration to the side of lower concentration.
How is passive transport thermodynamically favourable?
When something is transported down a concentration gradient it generates higher randomness, and therefore increased entropy.
This means that transport with the concentration gradient does not cost energy.
What is simple diffusion?
Solute diffuses through membrane with no protein required. (eg. oxygen and some lipophilic substances)
What is facilitated diffusion?
Diffusion of solute through channel or transporter (eg. glucose through GLUT). Some channels are regulated (gated)
List three types of concentration gradients
ions
molecules
protons (pH gradient)
Describe transport driven by ATP hydrolysis
Transporter is an ATPase, often called pumps.
Examples are Na/K pumps and H+ATPases which acidify organelles (like lysosomes)
Describe transport driven by ion gradient. List two types
Active co-transport
One solute is transported against its concentration gradient, but another one is co-transported down its gradient. Transport down the gradient drives the transport against the gradient.
Cotransporters (same direction, symport)
Exchangers (opposite direction, antiport)
What are two types of transporters for glucose? What is the point of having both types of these in a single cell?
Na glucose symport transports glucose against its concentration gradient and sodium down its concentration gradient (both into cell). Active co-transport driven by sodium gradient, can transport glucose even when there is lots of it in cell.
Glucose uniport (GLUT) is a passive transporter that transports glucose down its concentration gradient (always to side of lower concentration)
By having both of these in a single cell (but at different locations) there can be a direct movement of a solute (eg. glucose) in the cell from one part and out the cell at another. (eg. in absorption of nutrients into bloodstream at intestinal brush border cells)
What are membrane proteins and what two domains must they have?
Integral membrane proteins with extracellular and intracellular domains.
Generally a ligand binds to extracellular domain, which leads to a conformational change in cytosolic (intracellular) domain (leading to a cellular response)
What are three types of fat consumed in the diet?
Fat (traicylglycerols), phospholipids, cholesterol
TGs can’t cross membranes by simple diffusion, not soluble in water and in the diet in big droplets
What is the path a lipid takes to get into cells that need energy? (4)
Intestine
Enerocyte (intestinal wall)
circulation
cell
What is emulsification and where does it take place in body?
What acts as a detergent?
Big fat globules are broken down into small droplets (to increase surface area for exposure to lipase) in the intestinal lumen.
Bile acids from the gall bladder act as detergents.
What digests small fat droplets that have been emulsified by bile acids?
Pancreatic lipase
What is lipolysis?
Breakdown of triacylglycerols (TGs) by pancreatic lipase to form 2 fatty acids and 1 2-monoacylglycerol
Monoacylglycerols can be taken up by intestinal cells (enterocytes)
What is special about 2-monoacylglyerol?
It is hydrophilic and smaller, therefore can be transported across membranes. Intestinal cells can uptake monoacylglycerols
Describe phospholipid hydrolysis?
Different phospholipases hydrolyze different bonds in a phospholipid.
Phospholipase A
Phospholipase C
Phospholipase D
What bond does phospholipase A hydrolyze?
Releases fatty acids and lysophospholipid
What does phospholipase C do?
Removes headgroup with phosphate group
What does Phospholipase D do?
Removes headgroup without phosphogroup, makes phosphatidic acid
What are the 5 steps of transport of lipids from enterocytes (intestinal cells) into circulation?
- Uptake of hydrolyzed lipids (2 fatty acids and 1 monoacylglycerol)
- Resynthesis of triacylglycerols (2 fatty acids plus 1 monoacylglycerol combine to make 1 TG) in enterocyte
- Packaging of TG with some phospholipids, cholesterol and a specific protein into a lipoprotein particle (chylomicron)
- Secretion into lymphatic system through lymph duct
- Secretion into circulation
What is a chylomicron?
A lipoprotein particle formed in enterocytes, that house TGs, phospholipids, cholesterol and apoliprotein. Also cholesteryl esters
All for secretion into lymphatic and circulatory system
What do chylomicrons have in their shell? Is it amphipathic, hydrophobic or hydrophilic?
Phospholipid
Cholesterol
Apolipoproteins
Amphipathic
What do chylomicrons have in their core? Is it amphipathic, hydrophobic or hydrophilic?
Triacylglycerols
Cholesteryl esters
Hydrophobic
What are four major classes of plams lipoproteins in order of size?
Chylomicrons
Very Low Density Lipoproteins
Low density Lipoproteins
High density lipoproteins
What is the composition of chylomicrons and very low density lipoproteins (VLDL)?
85% triacylglycerols
9 % phospholipids
1-5% cholesterol
little protein, cholesteryl esters and others
What is the composition of Low density lipoproteins (LDL)?
5% triacylglycerol
50% cholesteryl ester
Where are triacylglycerols from? (two sources)
diet (chylomicrons)
liver to adipose (VLDL)
What type of cholesterol is in very low density lipoproteins?
Bad cholesterol from the liver
What type of cholesterol is in high density lipoproteins (HDL)?
Good cholesterol going to the liver
What are the primary apolipoproteins of chylomicrons and very low density lipoproteins (VLDL)?
apoB
apoC
apoE
What are the primary apolipoproteins of low density lipoproteins (LDL)?
apoB
What are the primary apoliproteins of high density lipoproteins (HDL)?
apoA1
apoE
What activates fatty acids in adipocytes?
CoA
How is fat stored into adipose tissue?
- TG-rich lipopoproteins (chylomicrons or VLDL) from diet or liver are exposed to lipoprotein lipase in blood circulation (capillaries of adipose tissue)
- Lipoprotein lipase hydrolyzes TGs into glycerol (stays in bloodstream) and 3 fatty acids
- These three fatty acids enter an adipocyte
- The fatty acids are activated by CoA and become fatty-acyl-CoA
- The 3 Fatty-acyl-CoA are then esterified with glycerol-3-phosphate (from glucose) into triacylglycerols (TGs)
How are LDL made and what are they?
They are cholesterol-rich lipoproteins that remain after hydrolysis of TGs from VLDL
What remains in the bloodstream after fat is stored in adipose tissue?
Chylomicron remnants (if TG from chylomicron ) or LDL (if TG from VLDL)
What type of lipoprotein can lead to atherosclerosis?
High levels of LDL can lead to atherosclerosis and a higher risk for heart disease
How is LDL in the bloodstream taken up?
First it deposits cholesterol in peripheral tissue. Then the liver takes up the rest of LDL by receptor mediated endocytosis.
Cardiovascular risk has a positive correlation with what types of serum lipoproteins and serum lipids?
LDL
LDL/HDL ratio
Serum cholesterol
Cardiovascular risk has a negative correlation with what type of serum lipoprotein?
HDL
What is an atheroma?
atheroma is an accumulation and swelling in artery walls made up of (mostly) macrophage cells, or debris, and containing lipids (cholesterol and fatty acids), calcium and a variable amount of fibrous connective tissue
What is the endothelium of an artery?
The inside cells of an artery.
What are 8 things that can cause chronic endothelial injuries?
Hyperlipidemia (elevated levels of lipids/lipoproteins in the blood)
Hypertension (high blood pressure)
Hyperinsulinimia (excess levels of insulin to glucose)
Smoking damage
Hemodynamic factors
toxins
viruses
immune reactions
What are the steps of atheroma formation? (8)
- Initial changes in endothelial lining of artery
- Monocytes adhere to enothelial cells
- Infiltration of monocytes into intima (second inside layer of artery wall)
- Differentiation of monocytes into macrophages
- Increased permeability for LDL
- Entry and retention of LDL into intima
- Modification of LDL (eg. mild oxidation)
- Uncontrolled uptake of LDL into macrophages and foam cell formation
What are the steps after atheroma formation that lead to cell death? (9)
- Smooth muscle cells migrate into intima and proliferate
- Further accumulation of lipids
- Increased synthesis of extracellular matrix (hardening of arteries)
- Beginning cell death
- — - Cell death begins with formation of necrotic core
- Calcium deposition
- Cholesterol crystal formation
- Plaque instability
- Plaque rupture
What is Nile Red dye used for?
To stain fatty lesion in arteries. Shows that high cholesterol diet leads to increased lesion area and occlusion of the arterial lumen
What is a chylomicron remnant?
A chylomicron with very little TG, taken up into the liver
Where from VLDLs from?
From the liver, carry TG and cholesterol.
How does hypercholesterolemia (high levels of cholesterol in blood) happen?
If LDL clearance is defective, high risk for heart attacks
What does HDL do?
High density lipoproteins mediate the transport of cholesterol form peripheral tissues back to the liver. The liver can excrete cholesterol from the body
How many direction does glucose move in the intestine?
Only one, from intestines to capillaries through the intestinal epithelial cell (enterocytes)
What is the injury model of atheroma formation?
- A chronic endothelial injury leads to inflammation and an injury response of the the endothelium
- Endothelial dysfunction sets in with increased permeability of the endothelial layer, leukocyte and monocyte adhesion, monocytes migrate into the intima
- Smooth muscle cell migration from media to intima and macrophage activation. Monocytes differentiate into macrophages upon adhesion to endothelium and migration into the intima, macrophages become activated due to increased cytokine release from endothelial and smooth muscle cells. Smooth muscle cells migrate into the intima.
- Lipid accumulation, macrophages and smooth muscle cells take up lipids without feedback control. The higher the LDL levels are in the plasma, the more lipid is deposited. HDL removes lipid form the arterial wall.
- Smooth muscle cell proliferation, extracellular matrix deposition, necrosis, deposition of extracellular lipids
- Calcification, calcium deposits in the arterial wall leads to hardening of the artery and increases the risk of plaque rupture
- Plaque instability, rupture of plaques releases the necrotic core and lipids into the blood stream: thrombosis
What is a thrombosis?
When plaque becomes so instable that it ruptures, releasing the necrotic core and lipids into the blood stream
What does pancreatic ligase do?
It hydrolyzes fatty acid ester bonds in triglycerides for uptake into the intestine.
