Lipoprotein Metabolism Flashcards
Lipoproteins
noncovalent lipid-proteins complexes that allow the movement of apolar lipids through aqueous environments like blood and lymph
How are lipoproteins classified?
according to their density, as determined by centrifugation.
How are lipoproteins separated?
Separation of lipoproteins on the basis of their buoyant density
-Buoyancy: Upthrust, is an upward force exerted by a fluid that opposes the weight
of an immersed object.
-Spinning (centrifugation) creates a gradient and will cause a settling of lipoproteins according to their density:
-High density = found at bottom (HDL)
-Low density = found at top (VLDL)
Describe the density of VLDL, IDL, LDL, HDL
The smaller the diameter the greater the density = less volume (mL) compared to mass (g)
The larger the diameter, the smaller the density (chylomicron = largest lipoprotein) = more volume (mL) compared to mass (g)
Lipoproteins are heterogenous in…
buoyancy and size but also in lipid and protein composition.
NOTE:
-The chart of protein composition is percentage of dry weight
-First 2 transport triacylglycerol, Last 2 transport cholesterol
-IDL is the link between the two transport systems, triacylglycerol (TAG) and cholesterol = it contains both TAG and cholesterol
The shell of lipoproteins is composed of
a single-layer of phospholipids, free cholesterol and proteins (apolipoprotein)
When we transport cholesterol we want it to be…
inert so it cannot integrate into the membrane so it must be bound to a free fatty acid (needs to be a cholesterol ester)
When we transport cholesterol we want it to be…
inert so it cannot integrate into the membrane so it must be bound to a free fatty acid (needs to be a cholesterol ester)
Name 2 lipoprotein transport pathways
- Endogenous
- Exogenous
Lipprotein Exogenous Pathway
Absorption and transport of fat (TAGs) and cholesterol from diet.
But also, reabsorption of recycled cholesterol (fecal cholesterol). (Liver takes the surplus of cholesterol we have and rejects it, so the cholesterol gets reabsorbed back into the intestine using this exogenous pathway)
Bile acids are derived from
cholesterol(Cholesterol = nonpolar molecule, so bile acids become much more polar and bile salts will now have a hydrophobic and hydrophilic side)
NOTE: Detergent action = hydrophilic face
Bile acids are derived from
cholesterol(Cholesterol = nonpolar molecule, so bile acids become much more polar and bile salts will now have a hydrophobic and hydrophilic side)
NOTE: Detergent action = hydrophilic face
2 primary bile acids synthesized by the liver are
- Cholic acid
- Chenodeoxycholic acid
Bile acids are further modified by
Adding taurine or glycine
How are primary bile salts formed
Primary bile acids conjugated to glycine and taurine in the liver will be combined to sodium and potassium salts to form bile salts.
How are secondary bile salts formed
Secondary bile salts are the result of the transformation of primary bile salts by the bacteria found in the colon.
Lipoprotein exogenous pathway steps (1-3)
- Bile acids are synthesized by the hepatocytes. They are stored in the gallbladder.
- Bile salts are released into the small intestine following a meal.
- The detergent action of the bile salts emulsifies lipids and generates micelles.
-An emulsion is a liquid which is a mixture of two or more liquids, such as oil and water, which do not naturally mix together.
NOTE: Bile salts coats TAGS and forms the outside of the micelle….hydrophilic faces outside and hydrophobic faces inside
Lipoprotein Exogenous Pathway (Steps 4-6)
- Dietary cholesterol and triacylglycerols (TAGs) will be absorbed by the bile salts micelles.
- The hydrophilic side of the bile salts will allow the recruitment of water-soluble enzymes.
-Pancreatic lipases and colipases. - The hydrolytic action of lipase and colipase will release fatty acids from the TAGs producing a mixture of glycerol, free fatty acids, monoacyl-glycerols and diacylglycerols.
Lipoprotein Exogenous Pathway (Stpes 7-8)
- Free fatty acids, monoacylglycerols and cholesterol will be absorbed by enterocytes lining the small intestine lumen.
-Free fatty acids and monoacyglycerol will be reassembled into TAGs. - A portion of cholesterol will be converted to cholesterol ester.
-An ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol.
-Cholesterol esters are less polar than free cholesterol
-This form of cholesterol is used for transport in plasma as well as a way to store cholesterol in a biological inert form
Lipoprotein Exogenous Pathway (Stpes 7-8)
- Free fatty acids, monoacylglycerols and cholesterol will be absorbed by enterocytes lining the small intestine lumen.
-Free fatty acids and monoacyglycerol will be reassembled into TAGs. - A portion of cholesterol will be converted to cholesterol ester.
-An ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol.
-Cholesterol esters are less polar than free cholesterol
-This form of cholesterol is used for transport in plasma as well as a way to store cholesterol in a biological inert form
Esterification of Cholesterol in cells is catalyzed by
Acyl-CoA:Cholesterol AcylTransferase (ACAT)
Lipoprotein Exogenous Pathway (Steps 9-10)
- Within the enterocytes, more precisely in the golgi apparatus, TAGs, cholesterol and cholesterol esters will be combined with apolipoproteins to form chylomicrons.
- Chylomicrons will be released into the lymphatic system and then, the bloodstream.
Apoliproteins
Apolipoproteins (apo) are proteins associated with lipoproteins where different lipoprotein classes contain different apolipoproteins.
Apolipoproteins can be subdivided into 2 categories
- Exchangeable apolipoproteins
- Non-exchangeable apolipoproteins
Exchangeable Apolipoproteins
Exchangeable apolipoproteins are tethered to the lipoprotein surface; they can dissociate from one lipoprotein particle and become associated with another lipoprotein particle.
-They are mostly composed of multiple amphipathic a-helices
Example: ApoE (don’t memorize just know examples from chart)
Non-exchangeable lipoproteins
Non-exchangeable apolipoprotein are tightly bound to a lipoprotein particle and do not dissociate from it.
-ApoB proteins are insoluble in aqueous solutions.
NOTE: ApoB (nonexchangeable) are much larger (molecular weight) than ApoE (exchangeable)
Non-exchangeable lipoproteins
Non-exchangeable apolipoprotein are tightly bound to a lipoprotein particle and do not dissociate from it.
-ApoB proteins are insoluble in aqueous solutions.
NOTE: ApoB (nonexchangeable) are much larger (molecular weight) than ApoE (exchangeable)
Lipoprotein Exogenous Pathway TAG Distribution
- After being secreted into bloodstream, chylomicron-carried TAGs are hydrolyzed by lipoprotein lipase; the released FAs are delivered to adipose tissue, and others organs.
- The liver takes up the resulting chylomicron remnants through endocytosis.
-Mediated by the ApoE and the LDL-receptor (LDLR)
-The ApoE ε4 (arg112, arg158) allele (13% frequency in pop.) was shown to play a role in atherosclerosis, Alzheimer’s disease, faster progression of multiple sclerosis (MS) and many more disorders.
-Remnants contain a small fraction of TAGs and cholesterol.
Hydrolysis of TAGS
When the lipoprotein lipase binds to Apo C-II it will activate the enzymatic activity of the lipase, so it will hydrolyze TAG to produce free fatty acids and glycerol
Lipoprotein endogenous pathway for TAG rich lipoprotein (VLDL)
- VLDL are synthesized in the liver (hepatocytes) via assembly of synthesized lipids (mostly TAGs) and apolipoproteins (e.g. apoB100, apoE, and apoCs)
- After being secreted into bloodstream, TAGs contained in the VLDL are hydrolyzed by lipoprotein lipase and the released FAs are delivered to adipose tissue (for storage) and other cells (for energy). (Slide 29)
- VLDL remnants (also called IDL or intermediate density lipoproteins) are taken up by the liver through endocytosis
-Mediated by the binding of ApoE to LDLR.
3 Fates of IDL
- IDL may be cleared from the blood stream by endocytosis in the liver
- IDL may go for a second round of bloodstream circulation.
- IDL may also exchange apolipoproteins and lipids with HDL to become LDL.
3 Fates of IDL
- IDL may be cleared from the blood stream by endocytosis in the liver
- IDL may go for a second round of bloodstream circulation.
- IDL may also exchange apolipoproteins and lipids with HDL to become LDL.
How IDLs become LDLs?
Exchange of Apolipoproteins and lipids between IDL and HDL.
IDL:
-Loss of ApoCI, II and III to HDL.
-Loss of TAG to HDL.
-Gain of cholesterol esters from HDL
HDL:
-Gain of ApoCI, II and III
-Gain of TAG from IDL
-Loss of cholesterol esters to IDL
LDL is what plugs
plugs your arteries and is what is known as the bad cholesterol
LDL is what plugs
plugs your arteries and is what is known as the bad cholesterol
3 biological functions of cholesterol
- structural component of cell membranes, particularly the plasma membranes
- constituent of lipoproteins
- precursor for bile acids and steroid hormones
Primary function of LDL
is to deliver cholesterol to extrahepatic tissues.
Uptake of plasma LDL is achieved by
the LDL receptor-dependent endocytosis
LDL receptor is an integral membrane protein that is expressed in the
liver and peripheral tissues
The LDL receptor-dependent endocytosis is part of the
regulatory mechanism for cholesterol homeostasis
Lipoprotein endogenous pathway for cholesterol-rich lipoprotein (LDL)
Endogenous pathway for cholesterol rich lipoprotein (HDL)
HDL Function
It has the opposite function of LDL:
-It removes cholesterol from tissues.
-Bring it back to the liver.
It is often called the HDL cycle or the reverse transport of cholesterol.
EXAM QUESTION: Can you describe the HDL Reverse Transport
YES next flash cards
HDL Cycle (Steps 1-3)
- Free apoA-I is secreted from the liver
- HDL precursors interact with the ABC-A1 transporter located at the cell surface of peripheral cells. At this step, they will acquire free cholesterol and phospholipids from the cell membrane to form disk-shaped nascent HDL
- Free cholesterol will be esterified by the action of LCAT leading to the transformation of the disk-shaped HDL into spherical mature HDL called HDL3
Esterification of cholesterol in cells is catalyzed by (HDL):
Lecithin:Cholesterol AcylTransferase (LCAT)
Esterification of cholesterol in cells is catalyzed by (HDL):
Lecithin:Cholesterol AcylTransferase (LCAT)
HDL Cycle Step 4-5
- The interaction of the HDL3 with the Cholesteryl Ester Transfer Protein (CETP) leads to a transfer of cholesterol ester to apoBs containing lipoproteins (VLDL, IDL and LDL).
- In the process, HDL will acquire new exchangeable apolipoprotein apoC-I, C-II and C-III as well as TAGs. This HDL is called HDL2
HDL cycle Step 6
6.Fate of HDL2: Selective uptake of CEs
-Liver and steroidogenic tissues (adrenal, testis, ovary) uptake of CE from HDL is mediated by SR-B1, resulting in the generation of ApoA-I /phospholipid complexes.
-SCARB1 (SRB1) = Scavenger receptor class B member 1
SUMMARY: Redistribution of fat (TAGs) and cholesterol throughout the body.
How many ATP and NADPH do I need to form 1 molecule of cholesterol starting from acetyl-CoA molecules?
- I need 18 acetyl-Coa to make a molecule of cholesterol
-Citrate lyase needs 1 ATP for each acetyl-Coa
-18 ATP - Stage 1 condensation
-HMG-CoA-reductase uses 2 NADPH/mevalonate (C6)
-I need the equivalent of 6 mevalonate/cholesterol
-Therefore, I need 12 NADPH at this step - Stage 1 condensation
-To form the activated isoprenes (DMAPP and IPP)
- I need to use 3 ATP/mevalonate
- Since it takes 6 mevalonate/cholesterol
- Therefore, I need 18 ATP at this step - Stage 2 polymerisation
-The condensation of 2 molecule of Farnesyl pyrophosphate into squalene required 1 NADPH - Stage 3 Cyclization
-The cyclization of squalene into cholesterol requires 13 NADPH - Total = 101 ATP
36 ATP
26 NADPH (At 2.5 ATP) = 65 ATP
