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Flashcards in Lipoprotein Metabolism Deck (30)

Storage of Energy Reserves

Lipids = 85%
Proteins = 15%
Carbohydrates =


Cholesterol, Phospholipids, and Triglyceride Structures

Cholesterol and cholesterol esters: fused ring system of hydrocarbons with OH group (only polar part that interacts with water)

Cholesterol esters are virtually insoluble

Attach FAs to three C glycerol backbone – how cells store fat; in order to make triglyceride

Phospholipids: similar to triglycerides, but no 3 FA, only 2 + phosphate; Lecithin: see as part of lipoproteins


Lipids in Blood

Fatty Acids: bound to albumin

Cholesterol, Triglycerides and Phospholipids
Transported by lipoproteins
Cholesterol can be free or esterified

Triglycerides must be degraded extracellularly to be absorbed by cells


Anatomy of a Lipoprotein

Inner core of tricylglycerols and cholesteryl esters
Outer shell: phospholipids with unesterified cholesterol



They are the unique structural determinants of lipoproteins
They serve as enzyme cofactors
They are ligands for binding to lipoprotein receptors



Contain dietary lipids (cholesterol, TG, etc); have B48 (not found in other lipids) and go through bloodstream and deliver cholesterol to cells



In liver, which manufactures fat on its own by turning glucose into fat and packages them into VLDL and ships into bloodstream; only has B100 when coming from the liver

VLDL dumps off TGs and turns into IDL and then LDL eventually (VLDL is precursor to LDL) and lost most TG and picks up cholesterol esters with only one protein component B100



Components come together in bloodstream from various sources; most unique protein is A1


TG and Cholesterol Carriers

Primarily TG carriers = VLDL and chylomicrons
Cholesterol carriers = LDL and HDL


Lipoprotein Lipase

Lipoprotein lipase (LPL): takes TG from chylomicrons and breaks down into FA and then stores in cells for later use
Once TG are gone, ApoC2 picked up by HDL you get a chylomicron remnant which goes to receptor on liver and endocytosed and dietary cholesterol

Extracellular enzyme on the walls of blood capillaries, anchored to the endothelium
TG is hydrolyzed to free fatty acids plus glycerol
Some of the released FFA enters circulation (bound to albumin) but most is transported into nearby tissue - mainly adipose, heart, and muscle (80%), while about 20% is transported to the liver


Receptors on Liver

Two types of receptors:
LDL receptor: takes in chylomicrons in liver and LDLLRP: LDL related protein; take in chylomicrons but must take out all TG first


Hepatic Lipase

HL is bound to the sinusoidal surface of liver cells
Hydrolyzes TG to free fatty acids plus glycerol (just like LPL)
Specific for chylomicron remnants and HDL


Liver and Synthesis of VLDL

Liver takes carbohydrates and makes TG and those are exported to make VLDL (mostly TG with B100 protein component with little cholesterol)

Goes through circulation to interact with liproprotein lipase and loses more and more TG and turned into IDL and ultimately LDL which then only has B100 and mainly cholesterol aka a cholesterol carrier and LDL delivers cholesterol to extra hepatic tissues or brings back to liver


LDL Endocytosis

LDL binds to receptors and endocytosed (endosome) and degraded into constituents and receptors are recycled back to surface to bind more LDL, but sometimes receptors are degraded to lower LDL intake

Once lipids inside, free cholesterol; cell can determine if needs cholesterol or not by having the receptors or synthesizing it by itself

Synthesis: once a lot of cholesterol, it will slow down synthesis and decrease production of LDL receptors

Pool of cholesterol can be converted to cholesterol esters for storage via ACAT


Eliminations of Free Cholesterol

No catabolic pathways to degrade cholesterol, and only way of getting rid of this is using liver to export to intestine
LCAT changes free cholesterol to cholesterol esters when free cholesterol is transported to HDL3 or HDL2
CETP: transfer cholesterol ester from HDL to VLDL, which VLDL rids TG to get LDL; ultimately HDL taken up by receptors on liver to get disposed (not well understood)



CETP: moves cholesterol ester from HDL into VLDL and at same time transfers TG from VLDL to HDL

Without CETP: VLDL would not be able to be made into LDL easily

Inhibitors of CETP = caused HDL levels to increase because unable to unload cholesterol esters, which also lowered LDLs; all drugs have failed in clinical trails thus far



LCAT: free cholesterol into cholesterol esters in HDL

ACAT: turns cholesterol into cholesterol esters intracellularly


Summary of Lipoproteins

HDL: comes from liver and intestine and has low TG and high cholesterol and delivers cholesterol from peripheral tissues to liver for elimination “cholesterol scavenger”

LDL: comes from VLDL has low TG and highest proportion of cholesterol that delivers it from liver to peripheral tissues “cholesterol donor”

VLDL: comes from liver and has high TG and low cholesterol; deliver endogenous (made in liver) TG to peripheral tissues

Chylomicrons: highest level of TG and transferred to peripheral tissues


Framingham Study: LDL and HDL Levels

Having low LDL and high HDL = best outcome for risk of CV disease

Less than 200mg/dl for total cholesterol
Women have higher HDL levels than men
HDL above 60 is lower risk
LDL: if at risk, recommended to be below 70

If lower LDL cholesterol, but HDL is not great then still at high risk; statins mainly target LDLs, but need to also impact HDL


Familial Hypercholesterolemia

Genetic defects causes problems in producing functional LDL receptors
Homozygous: no ability to produce LDL receptors no matter how low cholesterol gets and LDL skyrockets – very low lifespan
Heterozygous: some functional receptors


Unsaturated, Saturated, and Trans Fats

Saturated (single bonds) and trans are bad
Unsaturated (have double bonds) are good



Precursor from cell is acetyl-coA and then makes cholesterol via HMG reductase

Once cell has enough cholesterol it binds the enzyme to prevent conversion, but this can be insufficient and cell makes more cholesterol than it needs = where statins play a role to prevent cholesterol synthesis when feedback mechanism is not efficient enough

Statins also cause LDL bind to receptors and the cell is satisfying its need for cholesterol instead of the cell making its own cholesterol therefore lowering LDL levels in the blood (LDL is bad cholesterol so this is good)


Pleiotropic Effects of Statins

Improved endothelial function
Enhanced plaque stability
Decreased oxidative stress, inflammation, and thrombogenic response
Beneficial effects on immune system, CNS, and bone


Statin Side Effects

Muscle pain and damage (rhabdomyolysis)
Liver damage
Digestive problems
Rash or flushing
Increased blood sugar or type 2 diabetes
Neurological side effects


Half Life of Statins

Lipitor (atorvastatin) and Crestor (rosuvastatin) have the highest half lives of 14 and 19 hours, respectively
The others only have a couple hours



Works by different mechanism by inhibiting uptake of cholesterol in the gut by blocking the transporter
Vytorin = statin + uptake inhibitor aka simvastatin and ezetimibe

Vytorin compared to simvastatin = vytorin had significantly lower LDLs, but clinical outcome was worse for vytorin than simvastatin alone = vytorin plummeted


HDL and Niacin

Increasing HDL levels: HDL is returned to liver and taken out of circulation, but niacin inhibits this process (vitamin B3) at very high concentration = makes people feel hot and get red

Found no benefit to adding niacin when taking a statin to increase HDL


Statin Guidelines

New guidelines: obesity should be treated like a disease and new assessment of patients on whether they should take statins or not; if risk of 7.5% or greater for MI within the next 10 years, then put on statins

CV Risk Calculator: age, gender, race, total cholesterol, HDL, BP, treated for high BP, diabetic, smoker

Dilemma: if follow new guidelines, most people would be on statins; before guidelines total cholesterol over 200 then put on statins, the new guidelines are broader



PCSK9 influences if LDL receptors get recycled or destroyed in hepatocytes
Monoclonal Ab bind to PCSK9 to promote more recycling to lower LDL in circulation resulting in greater LDL uptake by liver cells and lower LDL cholesterol in the blood

LDL binds to receptor, endocytosed and turned into endosome and the receptor is removed from LDL particle and receptor is sent back to surface to bind more LDL
If enough cholesterol, produces PCSK9 which binds to LDL receptors causing prevention of recycling of receptors aka they are destroyed


Anti-PCSK9 Treatment

Monoclonal Ab administration: injection; since proteins, if taken orally, they would be broken down
Injections are once a week
Unproven clinical benefit for long term

FDA approved for familial hypercholesteremia so insurance companies cover it, but not for general population yet