Lecture 4- lipid particle metabolism

Question 1

what are some types of vascular disease

Answer 1

coronary heart disease, heart failure, stroke

Question 2

what factors contribute to vascular disease

Answer 2

calorific intake, lifestyle and genetics

Question 3

what is cholesterol needed for

Answer 3

membranes, vit D synthesis, calcium homeostasis, steroid hormones, bile synthesis

Question 4

describe the structure of cholesterol

Answer 4

27C molecule with a 4 ring steroid nucleus and an OH group on C3. it is amphipathic

Question 5

what is cholesterol synthesised from

Answer 5

acetyla coa

Question 6

how can high cholesterol be treated

Answer 6

using statins which bind hmgcoareductase to slow down production

Question 7

what are lipoproteins

Answer 7

complex aggregates of lipids and proteins that transport lipids through the PM mostly produced in the liver and intestine. they are composed mainly of triacylglycerols, free cholesterol, cholesterol esters and phospholipids. they have a polar surface to prevent super-aggregate formation

Question 8

what are the categories of lipoproteins

Answer 8

chylomicron, VLDL, IDL, LDL, HDL

Question 9

which lipoprotein is classed as “good”

Answer 9

HDL

Question 10

what is LDL responsible for

Answer 10

cholesterol transport from the liver to peripheral tissues

Question 11

what is LDL made up of

Answer 11

10% free cholesterol in outer layer, 40% cholesterol esther in core, small amounts (25%) of other lipids e.g. APOB100

Question 12

where is HDL synthesised

Answer 12

liver and intestine

Question 13

what is the content of nascent HDL

Answer 13

minimal lipid content and high ApoA1 content

Question 14

as HDL matures what does it do

Answer 14

it takes up cholesterol and phospholipids from extra hepatic tissues using ABCA1 transporters

Question 15

what is the effect of HDL inhibition of endothelial sphingosine kinase

Answer 15

inhibits activation of NFkB which inhibits production of adhesion proteins

Question 16

of which lipoprotein is apia! the main component

Answer 16

HDL

Question 17

describe the structure of APOA1

Answer 17

28kda, 243aa, 8a helices

Question 18

what are the 3 isoforms of APOE encoded by genetic polymorphisms and which are good and which are bad

Answer 18

APOE2 and E3 are good, ApoE4 is bad (found in alzhiemers patients

Question 19

what processes is ApoE involved in

Answer 19

lipid and lipoprotein homeostasis and lipid metabolism in the brain

Question 20

which lipoproteins are ApoB and ApoD found in

Answer 20

LDLs

Question 21

what is the role of APOB100

Answer 21

cholesterole ester needed for proper folding

Question 22

describe the lipid transport system

Answer 22

FABP binds fatty acids and monoacylglycerides and takes them to the ER where they meet ApoB48, forming a prechylomicron transport vesicle. it leaves the ER to the golgi where it binds APOE, APOC2 and APOA1. the prechylomicron matures into a chylomicron as a result and leaves the cell into the blood. Here lipoprotein lipase removes tiacylgyleceros, APOC2 and APOA1. the chylomicron remnant goes to the liver where an APOE component binds the LDL receptor. In the RER of the liver the lipid core binds APOB100 and reenters the blood stream. it binds AOC2 and APOE forming VLDL and moves into capillaries. lipoprotein protease again removes triacylglycerols and APOC2 forming an intermediate LDL. APOE is then removed making it an LDL. Oxidation of this results in uptake by cells including macrophages and liver cells.

Question 23

how is LDL taken up into cells

Answer 23

Binding of LDL via APOB causes clustering of receptors and forms clathrin coated pits. it is taken up in an endosome where it can then be delivered to the golgi or lysosome

Question 24

undershoot circumstances is HDl used

Answer 24

when fatty acids are not going to be used by the body

Question 25

describe the process of removal of fatty acids by HDL (reverse cholesterol transport)

Answer 25

ApoA1 is released from the liver into the blood and matures into pre b1 HDL. macrophages transfer cholesterol onto the HDL via the ABCA1 transporter which forms a pre b2 HDL. this matures into an a2 HDL which takes up triacylglyceride from LDL and transfers cholesterol esther to the LDL. The HDL then returns to the liver and binds the SRB1 receptor to deliver lipids and cholesterol for excretion in the form of bile.

Question 26

what is the cause of familial combined hyperlipidemia

Answer 26

mutations in apo A, B and E resulting in predisposition to heart disease

Question 27

what is the cause of Tangier disease

Answer 27

mutations in ABCA

Question 28

what are the roles of scavenger receptors

Answer 28

Key integral cell surface transmembrane proteins that bind to ligands Mediate pro-atherogenic response and uptake Mediates monocyte and macrophage differentiation Mediates endothelial responses Mediates vascular smooth muscle responses

Question 29

what is the role of scavenger receptor A and B

Answer 29

they mediate macrophage response. SRA binds ox-LDL causing MAPK and JNK signalling resulting in differentiation and SRB binds HDL also activating MAPK and eNOS pathway which protects the cells.

Question 30

what disease are mutations in LOX-1 scavenger receptor linked to

Answer 30

atherosclerosis

Question 31

what is the role of the LOX-1 SR

Answer 31

it binds ox-LDL, bacteria, dead cells and phospholipids and mediates a pro-atherogenic and pro-inflammatory response by the endotheliam

Question 32

what sort of stimuli up regulate LOX-1 receptor

Answer 32

pro-inflammatory signals

Question 33

what disease are LOX-1 KOs associated with

Answer 33

increased vascular and heart disease

Question 34

describe the development of atherosclerotic plaques

Answer 34

LDL crosses into the intima by scavenger receptors and is oxidised. binding of scavenger receptors results in signalling to produce VCAM which is a chemoattractant for monocytes and induces endothelial cells to up regulate expression of leukocyte adhesion molecules, increasing monocyte and T cell conc at the site. monocytes mature into macrophages which take up LDL via binding of scavenger receptors and become foam cells. ligand binding to TLRs on macrophages results in the production of pro inflammatory cytokines. this begins to form a necrotic core of foam cells and dead cells in a plaque which may rupture.

Question 35

what are the current therapies available for atherosclerosis

Answer 35

statins, surgery, small molecules (e.g. VB-201- inhibit monocyte chemotaxis) and gene therapy