Zusammenfassung der Ressource
Lipoproteins and lipoprotein transport
- LIPOPROTEINS
Anmerkungen:
- Non-covalent lipid and protein complex:
- PL (surface)
- TG (inside)
- CE (some inside, most on surface) --> always transports cholesterol as cholesteryl esters
- apo lipoproteins (integral)
- Less lipid=more protein=higher density=smaller diameter=lower mass; follow order above [big to small]
- APOLIPOPROTEINS
Anmerkungen:
- Integral proteins on lipoprotein surface that make them more soluble
- Apo A
Anmerkungen:
- I
Anmerkungen:
- - LCAT activator
- Structure (of HDL)
- Lecithin—cholesterol acyltransferase (LCAT) = enzyme that converts free cholesterol into CE (hydrophobic). Bound to HDLs n the blood plasma.
- LCAT levels affect overall lipoprotein concentration in an individual
- II
- IV
Anmerkungen:
- - LCAT activator
- Satiety
- Apo B
- 48
Anmerkungen:
- - Only on CM [48% of Apo B-100 is expressed from N-terminal]; upper limit to how big VLDL can be, can now be very large
- Structure of CM
- 100
Anmerkungen:
- - Structure
- VLDL, IDL, LDL
- LDLR ligand
- Made in liver
- Apo C
Anmerkungen:
- - Found in all types of lipoproteins EXCEPT for HDL
- Accessory type
- I
- II
Anmerkungen:
- Lipoprotein lipase activator
- III
Anmerkungen:
- Lipoprotein lipase inhibitor
- Apo E
Anmerkungen:
- - Found in all lipoprotein types EXCEPT for HDL
- Secondary ligand for LDLR [on liver] and VLDLR [i.e. VLDL remnants]
- Chylomicrons
Anmerkungen:
- - MAJOR LIPID COMPONENT =
TG
- From Intestines
- Travel to the lymphatic system, then the bloodsteam
Anmerkungen:
- Goes through adipose, cardiac, and skeletal muscle tissue before returning to liver
- Hydrolysis of TG by LPL
Anmerkungen:
- LPL in peripheral tissue capillaries
- CM Remnant
- Hepatocyte via remnant receptor
Anmerkungen:
- Contents released into cell
- Packaged again into VLDL
OR
- Excreted [SEE BELOW FOR LIVER EXCRETION VIA BILE]
- Free FAs
- Used for hepatic VLDL synthesis in liver
Anmerkungen:
- Transports endogenous TG, PL, UC and CE
- ENDOGENOUS PATHWAY
- Travels in the bloodstream
Anmerkungen:
- Goes through adipose, cardiac, and skeletal muscle tissue
- Hydrolysis of TG by LPL
- VLDL remnant =
- = IDL
- Back to liver via remnant OR LDL OR APO B/E receptor
- More hydrolysis by LPL
- LDL
- Modification and into peripheral cells via APO B/E receptor
Anmerkungen:
- Atheroma: accumulation of degenerative material in the inner layer of artery walls. The material consists of (mostly) macrophage cells, or debris, containing UC and FA
- Can get oxidated, more likely to accumulate in arteries
- Problem with APO B/E receptor [LDLR] on peripheral cells = FAMILIAL HYPERCHOLESTEROLEMIA
- HDL3 via ACAT [in cell]
Anmerkungen:
- intracellular protein located in the endoplasmic reticulum that forms cholesteryl esters from cholesterol.
- HDL2 via LCAT
Anmerkungen:
- CM via CETP
- aka nacent HDL
Nascent HDL: Obtains free cholesterol from peripheral tissues.
- LCAT promotes the uptake of free cholesterol by HDL [=esterification]
- CH -> CE = hydrophobic core, higher density of HDL
- CE transfer protein transfers CE from the HDL core and other circulating lipoproteins such as LDL.
- HDL2 <--> VLDL
HDL2 <--> CM
via CETP
- CM
- Digestion/Absorption in small intestine
- Fecal steroids
Anmerkungen:
- ABCG5/G8-->Similar to APCG1 but found on apical surface of the cell
responsible for removal of excess cholesterol and sending it out into the lumen for excretion
increase ABCG5/G8 expression(stimulated by LXR)--> more cholesterol exiting than entering cell
- Dietary fat, cholesterol
- EXOGENOUS PATHWAY
- VLDL via CETP
- Taken up by liver via HDL OR LDL receptor
Anmerkungen:
- SEE HOW LIVER GETS RID OF EXCESS CH BELOW
Lipoprotein CH exist as CE and get degraded once inside enterocyte to contribute to UC pool [free CH pool]
- Back to liver via LDL receptor
Anmerkungen:
- Problem with LPL = Hypertriglyceridemia and the metabolic syndrome
Anmerkungen:
- Problem with CD36 to take in FA from VLDL in peripheral cells =
METABOLIC SYNDROME
- Free FAs
- Stored in peripheral tissues via CD36 receptor
- VLDL
Anmerkungen:
- - MAJOR LIPID COMPONENT =
TG
- From liver
- IDL
Anmerkungen:
- - MAJOR LIPID COMPONENT =
CE
- From Catabolism of VLDL
- LDL
Anmerkungen:
- - MAJOR LIPID COMPONENT =
CE
- "BAD" cholesterol
- From catabolism of IDL
- HDL
Anmerkungen:
- - MAJOR LIPID COMPONENT =
PL
- "GOOD" cholesterol [still same CH moiety as LDL]
- From Liver and intestine
- Can separate by charge [NOT SIZE] via agarose gel electrophoresis
- Pre-beta mobility = VLDL
Anmerkungen:
- Only for non-fasting individual
- Alpha mobility = HDL
Anmerkungen:
- Beta mobility = LDL
Anmerkungen:
- Closest to origin [=CM, no mobility]
- Fate of Cholesterol
Anmerkungen:
- Waxy fat carried thourgh the bloodstream by lipoproteins
- "GOOD" = HDL
Anmerkungen:
- - Stable, carries CH away form arteries
- Actively soak up CH in peripheral cells, bring to liver for reuse or removal
- - Travel in bloodstream, picking up CH [stays on outer layer
- LCAT on skin of HDL, gets activated by apo A1, convert CH into CE
- CE can go into HDL particle = disk becomes bigger and bigger
- Reverse cholesterol transport
Anmerkungen:
- http://www.medscape.org/viewarticle/479499_3
- Some organisms can't do reverse transport due to no CETP
- Pathway NOT binary, can go back and forth.
Depends on genotype and proteome & environment determines whether used or not.
- Peripheral cells
Anmerkungen:
- - More interactions with ABCA1 on the surfaces of macrophages in the arterial wall, apoA-I removes excess cholesterol from these macrophages
--> Free cholesterol in peripheral cell [adipose/muscle tissue] finds way to membrane, and travels to apo A1 surface= nascent pre-beta HDL, or HDL2 particles
- Transport probably chaperoned, organizes membrane composition to allow for transport OR can interact with apo A1 [on HDL] to create bridge
- HDL2 --> HDL3
Anmerkungen:
- LCAT converts UC to CE [hydrophobic], so will enter the interior of the HDL2 particle = "mature" HDL [HDL3]
- If not converted to CE, can go back to peripheral cell membrane.
- HDL2 can also take CE from LDL
- This conversion is done when there is low HDL levels in the blood
- LDL
Anmerkungen:
- Via CETP:
CE : HDL3 --> apo B lipoproteins (remnants, VLDL, IDL, LDL via CETP)
TG : apo B LP --> HDL3
- Liver parenchymal cells [into UC pool of membrane]
Anmerkungen:
- - HDL3 is selectively taken up by the liver via SR-B1
OR
- CE within apoB-containing lipoproteins is transferred to the liver through interaction with hepatocyte LDL receptors.
- THE ONLY ORGAN IN THE BODY THAT CAN PROCESS CHOLESTEROL FOR REMOVAL FROM THE BODY
All other cells can only process small amount of cholesterol; some use more if used to make other products ex: testes, ovaries to make hormones
- The amount of free cholesterol is tightly controlled by the cell; maintain set point in cell membrane. If too much then several mechanisms come into play to remove extra cholesterol in the cell.
- Hepatic Lipase
Anmerkungen:
- Lipolytic enzyme, role in HDL metabolism. Partly regulates CH levels.
HL hydrolyzes TG and PL in HDL + stimulates CE uptake from HDL by hepatocytes. HL and lipid transfer proteins determine both HDL-cholesterol level and its function in reverse cholesterol transport.
- Disposal of CH through bile
Anmerkungen:
- CE from HDL3 and LDL through reverse CH transfer [now free CH in liver[ is disposed through bile
- 2 main pathways used by the liver to get rid of excess CH [most efficient]
- Bile Acids
Anmerkungen:
- - Involves Cyp7a1 [RL enzyme]
- UC used to synthesize bile acid cannot go back into cycle [i.e. cannot revert back to CH]
- Goes to gallbladder for storage [to emulsify dietary lipids in small intestine]
- Alsoacts as signlaing molecules
- Recapturing by liver from blood for reuse
Anmerkungen:
- Can't metabolize CH and reinvest energy used, converting costs MORE energy
Acetyl coA -> BA = lots of ATP
so body recaptures BA and brings back to liver for usage again 3+ times more
- Biliary CH
Anmerkungen:
- - Looks just like dietary cholesterol/lipid SO can go back into liver
- Used to collect things not wanted in body
- Also released into lumen of small intestine to emulsify dietary lipids [signaled by cholecystokinin in SI]
- Storage as CE in lipid droplets
Anmerkungen:
- Only way peripheral cells can get rid of excess cholesterol BUT only small role in liver cells [have other more efficient ways]
- Lipoprotein assembly = VLDL
Anmerkungen:
- Once too much CE stored in lipid droplets, used to make VLDL [high in CE]
- Excess HDL can transfer CE to VLDL in exchange for TG via CETP
- Apo A1
Anmerkungen:
- - ApoA-I is synthesized by the liver, interacts with ABCA1 in the hepatocyte
- Secreted into the plasma as a lipid-poor particle and travel to peripheral cells
- Problem with ABCA1 transporter in peripheral cells giving away TG to go from HDL2 to HDL3 =
TANGIER DISEASE
- "BAD" = LDL
Anmerkungen:
- - Atherogenic
- Sticks to artery walls and contributes to plaque build up
- Also accumulates in peripheral cells like smooth muscle
- Carry the majority of the CH in the blood, supplying cells
- LDL receptors in peripheral cells or liver bind with LDL and clear it from the blood
- Peripheral cells utilize LDL cholesterol for cell membrane structure and the production of hormones
- Excess CH in peripheral cells due to oxidized LDL, more likely to be deposited into the artery wall.
Attract macrophages that eventually cannot handle too much free UC and die = plaque
- Binding of CM and LpL to GPIHBP1 at the Endothelial Cell Surface
Anmerkungen:
- - CM and LPL bind to opposite acidic domain of GPI anchors [adjacent]
- Brought closer together, domains interwine and CM degradation by LPL = free FA
- FA goes into the cell via albumin