Lecture 11- lipoproteins

chylomicrons

carry lipids from intestine into the blood compartment due to its size

VLDL comes from where?

the liver

LDL

disposes cholesterol 

HDL 

remove excess cholesterol 

lipoprotein metabolism- 3 pathways 

exogenous, endogenous, and reverse cholesterol transport; very dynamic pathways, proceed simultaneously

exogenous pathway

how we transport lipids in a chylomicron boat from our intestine into the blood and distribute it to different tissues 

lipoprotein lipase 

physically interact with a chylomicron particle and work to chop up all the TGs that are in the boat which allows all the fatty acids to be released 

chylomicron remnant

less TGs, much smaller, ApoE and ApoB-48

what enzymes are on chylomicron

ApoB-48, ApoC-II, and ApoE

importance of lipoprotein lipase

feed-forward disposal of dietary and endogenous FA, lipoprotein ‘remodeling’, TG hydrolyzed progressively- DAG to MAG to FFA

lipoprotein lipase- required cofactors 

activated by apoCII, comes from HDL, stimulates lipoprotein lipase; inhibited by apoCIII

consequences of lipoprotein lipase deficiency 

have an increased amount of TGs

lipoprotein lipase- adipose tissue

stimulated by insulin, high Km, high during postprandial state, low during fasting

lipoprotein lipase- muscle tissue

inhibited by insulin, low Km, low during postprandial, high during fasting

endogenous pathway

lipids that we make in out bodies ourselves, VLDL from liver make LDL particles

enzymes on VLDL particles

ApoB-100, ApoE, and ApoC-II

enzymes on LDL

ApoB-100

every cell has the ability to

take up cholesterol from the blood, which is important because this synthesis pathway is extremely energy demanding

unesterified (active) cholesterol pool- inputs

cholesterol synthesis, CE hydrolase, HDL, and LDL

unesterified (active) cholesterol pool- outputs

in cell acyl-coenzyme A (CoA) cholesterol acyltransferase (ACAT); in blood lecithin-cholesterol acyltransferase (LCAT)

when is cholesterol being synthesized

postprandial state

cholesterol synthetic pathway- intracellular location

multiple tissues including cytosol and ER

cholesterol synthetic pathway- highly complex

30 different reactions, 20 enzymes, energy expensive process

cholesterol synthetic pathway- starting point

all carbons come from acetyl-CoA

cholesterol synthetic pathway- regulatory point 

HMG-CoA reductase, most heavily regulated enzyme

cholesterol synthetic pathway- activity 

inversely proportional to cellular cholesterol 

LDL receptor pathway- step 1

LDL particle binds to LDLr (ApoB-100)

LDL receptor pathway- step 2

endocytosis receptor + LDL particle, pumps H⁺ to lower pH, receptor-mediated endocytosis

LDL receptor pathway- step 3

separation of LDL particle from receptor, LDLr recycles back to cell surface

LDL receptor pathway- step 4

endosome fuses with lysosomes, breakdown fat and PN

LDL receptor pathway- step 5

cholesterol sorted into cell compartments

reverse cholesterol transport ApoA-I

the protein component on an HDL particle and is made in the liver, secreted into the blood, pick up excess cholesterol and grows into PreB HDL which eventually goes back to the liver

reverse cholesterol transport ABCA1

works to take cholesterol that’s inside a cell and put it out onto an HDL particle

LCAT (lecithin cholesterol acyltransferase) 

esterfies and therefore traps cholesterol in HDL, significant role in the formation of mature HDL

SR-B1 (scavenger receptor B1)

selective lipid uptake (contrast this with the LDL receptor)