Lipoprotein Metabolism II

Question 1

What cells is microsomal triglyceride transfer protein (MTP) found in?

Answer 1

hepatocytes and intestinal cells

Question 2

What part of the cell is MTP found in?

Answer 2

ER lumen

Question 3

What is the function of MTP?

Answer 3

transfers newly formed lipids from the ER membrane to APOB (APOB100 in the liver and APOB48 in the gut) in the first step of lipoprotein formation, and continues to add particles to the growing lipoprotein

Question 4

What is the structure of MTP?

Answer 4

heterodimer comprised of a large subunit and a protein disulfide isomerase (PDI)

Question 5

What does PDI do in MTP?

Answer 5

helps maintain the large subunit in soluble and also help transfer the MTP to the ER after its translated

Question 6

What does the large subunit in MTP do?

Answer 6

lipid transfer activity from the ER membrane to APOB

Question 7

After chylomicrons are first assembled in the ER, what happens?

Answer 7

they are transferred in a PCTV (pre-chylomicron transfer vesicle) to the Golgi where it docked and the chylomicrons are altered slightly

Question 8

Is the transfer of chylomicrons from the ER to the Golgi microtubule dependent or independent?

Answer 8

independent

Question 9

How do nascent chylomicrons leave the golgi to be released from the basal lamina of the enterocyte into lymphatic circulation?

Answer 9

they are secreted in vesicles in a microtubule-dependent fashion

Question 10

What is the significance of chylomicrons leaving the golgi in a microtubule-dependent process?

Answer 10

this step can be inhibited with drugs like Cholchicine

Question 11

How does the exogenous lipid pathway work?

Answer 11

Intestinal cells secrete chylomicrons with Apo48 and ApoA1 (and Apo A4). AoB48 will stay with the chylomicron throughout the complete cycle. HDL particles transfer ApoCII and ApoE to the chylomicron. ApoCII interacts with an LPL receptor on adipose. LPL acts on the chylomicron to release fatty acids (to muscle for energy and adipose for storage). Once this happens, ApoCII and ApoA1/4 are recycled to HDL (Apo48 and ApoE remain with the remnant chylomicron). The cycle continues until the remnant chylomicron is recycled to the liver where the ApoE protein interacts with LRP for uptake. Cholesterol in the liver can then stored, secreted, made into bile acids, etc.

Question 12

How does the endogenous lipid pathway work?

Answer 12

The liver synthesizes VLDL particles with ApoB100, ApoA, ApoE, and ApoCII. The liver also secretes a fair amount of HDL with ApoA, CII, and E. When the VLDL is released, HDL gives some ApoCII and ApoE (but not much since the liver can make its own), and then the VLDL goes to adipose where TAGs are removed via LPL and the VLDL becomes smaller and forms an IDL. IDL can be taken by LDL receptors, but in humans they tend to recirculate until they are LDL (which only have APo100- all others are recycled to HDL), and are then taken up into tissue (50% to the liver, and other peripheral tissue). Cholesterol from the LDL are then stored, secreted, made into bile acids, etc similar to the end of the exogenous pathway

Question 13

What does ApoC3 do?

Answer 13

it inhibits uptake of IDL by LDL receptors to increase recirculation of IDL particles

Question 14

Who does the reverse cholesterol transport (ak HDL pathway) work?

Answer 14

De novo HDL particles are made in the liver and effluxed via ABCG1 pumps (along with ApoA1; they do not have cholesterol esters so they are flat). As they circulate, ABCA1 and ABCG1 pumps efflux free cholesterol from peripheral tissue and vasculature into the bloodstream. APOA1 activates LCAT to esterify the cholesterol to fatty acids from lecithins to make the HDL circular. CTEP transfers some cholesterol to VLDL and iDL in exchange for TAGs. The HDL is then recycled to the liver and taken up via SR-B1 receptors and any TAG in the HDL is removed via hepatic TAG lipase (HTGL). This process helps prevent cholesterol accumulation to periphery tissue and vascular walls.

Question 15

What does Cholesterol Ester Transfer Protein (CETP) do?

How is it related to Metabolic Syndrome?

Answer 15

exchanges cholesterol in HDL for TAGs in VLDLs and IDLs.

In Metabolic syndrome CETP is too active and you get an increased amount of cholesterol in VLDL and IDL (which makes it LDL) which ain’t good and shit

Question 16

Does fasting affect TAG levels? Cholesterol, LDL, and HDL?

Answer 16

TAG- yes

Cholesterol and LDL and HDL- NO

Question 17

What things are obtained in a fasting-lipid profile?

Answer 17

total cholesterol
total TAG
HDL-choelsterol

Question 18

How can HDL, LDL, and VlDL cholesterol levels be measured directly?

Answer 18

ultracentrifugation (takes several days)

Question 19

How can you estimate LDL-cholesterol levels from a fasting lipid profile?

When is this valid?

Answer 19

the Friedewald equation

LDL (mg/dL)= total cholesterol - HDL - TAG/5 (mg/dL) or

LDL (mmol/dL)- total choelsterol- HDL- TAG/2.2

not valid if TAG > 400 mg/dL and has to be done in the fasting state

Question 20

MOST cholesterol is found in what particle?

Answer 20

LDL (good if in low levels, bad if high)

Question 21

What is an ideal level of cholesterol?

Answer 21

200 mg/dl. As levels approach 302 mg/dl you are more likely to have an inherited deficiency in cholesterol uptake

Question 22

What is an ideal level of TAG?

Answer 22

200mg/dL. levels approaching 1000mg/Dl increase the risk of pancreatitis

Question 23

What s familial hypercholesterolemia caused by?

Answer 23

autosomal dominant disease caused by a defective LDL receptor

Question 24

How do LDL receptors work?

Answer 24

LDL receptors internalize LDL particles via interaction with Apo100. LDL particles go into a lysosomal compartment where it is broken down. The free cholesterol is then re-esterified via ACAT for storage. This entry down regulated cholesterol synthesis and LDL receptor synthesis. LDL receptors then recycle back to the cycle surface to internalize more

Question 25

What is the structure of the LDL receptor?

Answer 25

Has an external ligand binding domain for Apo100 (with a transcription signal domain), an epidermal growth factor precursor homology domain, an O-linked sugar domain, a membrane spanning domain, and then a cytoplasmic domain inside the cell

Question 26

What happens if there is mutation/deletion of the cytoplasmic domain?

Answer 26

decreased internalization

Question 27

What happens if there is mutation/deletion of the membrane spanning domain?

Answer 27

receptor is secreted from the cell and not anchored

Question 28

What happens if there is mutation/deletion of the O-linked sugar domain?

Answer 28

No effect

Question 29

What happens if there is mutation/deletion of the epidermal growth factor homology domain?

Answer 29

decreased recycling of LDL receptor and transport through the cell

Question 30

What happens if there is mutation/deletion of the Apo100 binding domain?

Answer 30

decreased Apo100 binding and LDL transport through the domain

Question 31

How do statin drugs work do prevent hypercholesterolemia?

Answer 31

a SCAP particle in the ER of a cell senses the levels of oxycholesterol caused by statin inhibition of HMG CoA reductase and it cleaves a SREBP precursor from the ER into the golgi of the cell, where the SREBP is converted to its active form. The active SREBP moves to the nucleus to initiate transcription of more LDL receptors. Increased LDL receptors help internalize more LDL and thus, lower blood cholesterol levels

Question 32

What is Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9)?

Answer 32

A protein that can down regulate the recycling of LDL receptors from the cell surface and rice to a degradative pathway via lysosome. So, blood cholesterol increases

Question 33

What do drugs like alirocumab and evolocumab do?

Answer 33

inhibit the action of PCSK9 to help treat hypercholesterolemia

expensive AF

Question 34

What is Apo little a?

Answer 34

promote clot formation of athersclerenic plaque

Question 35

How does atherosclerosis occur?

Answer 35

Starts with injury to the lining of a blood vessel (from BP, diabetes, exposure to LDL) and then LDL enters the cell where it is oxidized. Oxidized-LDL can further injury the cell wall, which use macrophages to help the injury. Macrophages bind oxidized-LDL and internalize it (not regulated!! so it will take up a lot). Macrophages with oxidized-LDL form ‘foam’ cells which further produce cytokines and stimulate further injury the the cell lining. The macrophages produce smooth muscle cells which forms collagen and then they moves up to form plaque, with the collagen forming a cap over the macrophages. Collagenases can then break down the collagen cap, releasing LDL, which is then acted upon by platelets- thus increasing the risk of heart attack via clot formation