Hyperlipidemia I Flashcards
What is hyperlipidemia?
Why is it a concern?
What are the primary & secondary causes?
elevated levels of lipids int he blood (cholesterol & triglycerides)
leads to increased risk of atherosclerotic cardiovascular disease (ASCVD)
- Primary cause: genetic conditions
- secondary causes: environmental factors (diet, exercise etc)
What is the difference between the exogenous and endogenous lipoprotein metabolic pathways?
- Exogenous pathway: transports dietary lipids to the periphery & the liver
- Endogenous pathway: transports hepatic lipids to the periphery
Identify the full term for the following acronyms:
FFA
HL
IDL
LDL
LDLR
LPL
VLDL
- FFA
- free fatty acid
- HL
- hepatic lipase
- IDL
- intermediate-density lipoprotein
- LDL
- low-density lipoprotein
- LDLR
- low-density lipoprotein receptor
- LPL
- lipoprotein lipase
- VLDL
- very-low-density lipoprotein
Check out this table! Pick a section & write it down
check this out! Pick a section & write it down
Which lipids are transported by lipoprotein particles?
Which lipids are transported by albumin?
- Lipoprotein particles
- triglycerides
- phospholipids
- cholesterol & cholesterol esters
- Albumin
- Free Fatty Acids
What are some examples of lipids?
What is a lipoprotein & provide some examples?
What is an apolipoprotein & provide some examples?
-
Lipids
- cholesterol and cholestrol esters, triglyceride, fatty acids, phospholipids
-
Lipoprotein: lipid transport particles in the blood
- chylomicron, chylomicron remnants, VLDL, IDL, LDL, HDL
-
Apolipoprotein: protein subunits of the lipoprotein particle
- ApoB48, ApoB100, ApoC11, ApoA-1
What is the function of the following lipoproteins
chylomicrons
VLDLs
LDLs
HDLs
-
chylomicrons
- transport dietary fat from the intestine
-
VLDLs
- transport endogenous fat from the liver
-
LDLs
- deliver cholesterol to liver and tissues with large cholesterol needs (adrenals, sex glands, etc.)
-
HDLs
- transport cholesterol from membranes in tissues to IDLs which deliver cholesterol back to liver
What are the “good cholesterol” and the “bad cholesterol” ?
- Good Cholesterol
- HDL : reverse cholesterol transporter
- Bad Cholesterol
- LDL: 40-50% cholesterol
Identify the indicated components of the lipoprotein particle
- Core: nonpolar lipid (triglycerides & cholesterol esters)
- Surface: phospholipids, cholesterol and other amphipathic molecules (i.e. apolipoproteins)
-
Apolipoproteins
- some functional, some structural (as synthesizing particle)
- activate enzymes
- act as ligands for receptors
List the lipoproteins in order from largest to smallest
Which are most bouyant?
- Largest to smallest
- chylomicrons
- VLDL
- IDL
- LDL
- HDL
- lipoproteins that contain the highest percentage of neutral lipid (like triglyceride) are more bouyant
What are the relevant structural scaffold apolipoproteins? Functions?
What are the relevant apolipoproteins that activate enzymes or bind to receptors? Functions?
- Structural scaffold apolipoproteins
- Apo B-48 Chylomicrons
- Apo B-100
- VLDL, IDL, LDL
- provide structure & assist in binding receptors (chylomicron remnant receptor and LDL receptor)
- Apolipoproteins that activate enzymes or bind to receptors
- Apo A-1
- HDL, Chylomicrons, VLDL
- Activates LCAT
- Apo E
- chylomicron remnants, VLDL, IDL, HDL
- acquired from HDL particles in teh blood & binds to the ApoE receptor on the liver
- ApoC-II
- chylomicrons, VLDL, IDL, LDL
- acquired from HDL particles in the blood, binds and activates lipoprotein in lipase in muscle and adipose tissue
- Apo A-1
Describe the exogenous lipid pathway from ingestion to blood stream
- Dietary Lipids (exogenous)
- solubolized by bile salts
- pancreatic lipase & colipase converts it to 2-momoacylglycerol (2-MG)
- 2-MG taken up by epithelial & put back together into a triglyceride
- add apoB & phospholipid layer
- secreted into lymph as chylomicron
- join the blood stream via the thoracic duct
Describe the endogenous lipid pathway from production to blood stream
- Endogenous (liver)
- excess fuel becomes acetyl CoA, which can be use to generate fatty acids & ultimately triglycerides
- (VLDL) will be constructed with tryglycerides, apoB, and phospholipids & secreted by the liver directly into the blood stream becaue the liver has breaks in the endothelium
Identify what the following molecules carry, where they are made, what they are packaged with, and where they go after secretion
Chylomicrons
VLDLs
LDL particles
- Chylomicrons
- carry dietary lipid
- synthesized by intestinal epithelial cells
- packaged TG and dietary cholesterol with apoB-48
- move via the lymph through the thoracic duct
- VLDLs
- carry endogenous lipid from the liver
- synthesized in the liver
- contain cholesterol de novo synthesis derived from dietary carbohydrates
- packaged TG, cholesterol and apoB-100
- after secretion into the blood, VLDLs are converted to IDLs and eventually LDLs
- LDL particles
- cholesterol-rich transport particles
- internalized by the liver adn othe rtissues needing large amounts of cholesterol (ie. adrenals for steroid synthesis)
Draw this summary
Describe the transport of exogenous lipids by chylomicrons
- Dietary triglycerides coming into the small intestine
- VLDLs synthesized in epithelial cells & they go out into the lympatics
- at this point they are nascent (Apo-B48 & Apo-A)
- Nascent chylomicron can interact with HDL which will transfer the ApoC & ApoE making it a mature chylomicron
- ApoC activates lipoprotein lipase when it gets to the extrahepatic tissues (adipose & muscle) that allows for the removal of triglycerides by digesting it to fatty acids (taken up by the cells) & glycerol (back to the liver)
- After losing triglycerides, the chylomicrons become smaller, more dense & lose apoproteins at which point they are considered a chylomicron remnant
- they will be taken up by the liver & digested
Describe the transport of endogenous lipids via VLDL
- Fatty acids converted to triglycerides, which are then packaged into VLDL
- VLDL goes out into blood stream where it picks up CII (activate lipoprotein lipase) & E from HDL
- Fatty acids (muscle will convert FA to CO2 + H2O & adipose will convert FA to TG stores) & glycerol will leave
- the VLDL loses enough fatty acids, it will be converted to an IDL
- some of the IDL will pass by the liver & endocytosed, go to lysosomes and be degraded
- some IDL will interact with other lipases (i.e. HTGL), losing more FA & becoming LDL
- LDL can be endocytosed by the liver, gonads or adrenals to be degaded & reused
- If there is a lot of LDL sitting around for a while, it can sneak into the intima of the blood vessels where macrophages will try to clear it up & in the process create foam cells
What is the major concern with the development of foam cells?
cells with huge amount of fat inside are the precursors for atherosclerosis
Describe the process of LDL receptor-mediated endocytosis
- Binds to the receptor in a clathrin-coated pit
- endocytosed by pinching off membrane & creating vessicle
- this vessicle becomes an endosome
- receptor will enter different particle to be recycled back to the cell membrane
- drop off the particle
- the lipoprotein particle will join with a lysosome which will breakdown fats to FA and cholesterol (to membrane or cholesterol ester droplets), proteins to AA
- Additional receptors are processed through the ER & golgi then sent to the membrane
What are the 4 possible fates of endocytosed cholesterol?
- Incorporated in plama membrane
- Stored as cholesterol ester
- Used for biosynthetic purposed
- bile salts
- hormones
- Used as regulatory signal
- inhibits HMG CoA reductase synthesis (RL step in cholesterol synthesis)
- Inhibits LDL receptor synthesis
- Stimulates ACAT activity
How is cholesterol stored?
What are the two enzymes used for this conversion?
- Cholesterol is stored as cholesterol ester
- ACAT (acyl:cholesterol acyltransferase)
- synthesized at the tissues
- esterfires fatty acid (from fatty acyl CoA) to cholesterol in cells
- located in the cytosol of cells that store cholesterol
- LCAT (lecithin:cholesterol acyltransferase)
- synthesized int eh blood
- esterfies a fatty acid (obtained from lecithin) to cholesterol present within HDL particles
- located in the serum
- activated by the Apo-A1 on teh HDL particles
What do cells do with excess cholesterol?
Why do they do this?
They can stick it on the outer leaflet of the plasma
- Because as HDL (which is produced by the liver) goes by these cells, it will take up extra cholesterol from cell membranes
- The LCAT will convert the cholesterol to a cholesterol ester
- it will interact with a VLDL or IDL through cholesterol ester transferase protein (CETP)
- it will trad cholesterol esters for tryglycerides or phospholipids from these molecules
-
Purposes of this exchange
- feeding LCAT new substrate,
- replacing what LCAT has burned making cholesterol ester
- removing extra surface area from VLDL as you are shrinking the particle
Nam the substates & enzymes involve in producing a cholesterol ester
Have to use a fresh phospholipid for every LCAT reaction (b/c always use C2)
