Lipoprotein Metabolism

Question 1

sphingomyelin

Answer 1

Lipid with structure highly analogous to phospholipids

Instead of a glycerol backbone, there is a serine amino acid derrived nitrogen connected to a carbon tail

Fatty acid group can be linked to nitrogen to form a ceramide

Important signal transduction molecule

Question 2

cholesterol

Answer 2

a sterol which serves critical functions in maintaining membrane fluidity and serving as a precursor molecule to steroid hormones

an important derivative is the cholesteryl ester

Question 3

HMG-CoA reductase

Answer 3

an enzyme which leads to the synthesis of mevalonate, the basic building block of the sterol moiety

the rate limiting step of the cholesterol biosynthesis pathway

Question 4

main classes of lipids

Answer 4

fatty acids

triglycerides

phospholipids

cholesterol

Question 5

typical lipoprotein structure

Answer 5

apolipoproteins

amphipathic surface - mostly phospholipids and cholesterol

hydrophobic core - triglycerides and choleteryl ester

Question 6

purpose of lipoproteins

Answer 6

deliver fats as fuel

cholesterol transport

phospholipid transport

Question 7

roles of apolipoproteins

Answer 7

cofactors for enzymes and receptors, conferring specificity

structural scaffolds - acts as a belt to hide the hydrophobic tails of the phospholipids

acts as a cofactor for ABCA1, which is important for transferring cholesterol to apolipoproteins

Question 8

major lipoprotein classes

Answer 8

chylomicrons

chylomicron remnants

very low density lipoproteins (VLDL)

intermediate density lipoproteins (IDL)

low density lipoproteins (LDL)

and high density lipoproteins (HDL)

Question 9

key pathways of lipoprotein transport

Answer 9

exogenous pathway

endogenous pathway

reverse cholesterol transport

enterohepatic circulation

Question 10

key enzymes of lipoprotein transport

Answer 10

lipoprotein lipase (LPL)

lecithin-cholesterol acyltransferase (LCAT)

cholesteryl ester transfer protein (CETP)

Question 11

exogenous pathway

Answer 11

the process by which chylomicrons delivered from the gut via the thoracic duct mature, deliver tryglycerides to peripheral cells, and are then taken up by the liver

critical to converting triglycerides to free fatty acids is lipoprotein lipase, which is found on the endothelium

Question 12

enterocyte package

Answer 12

triglycerides

cholesterol

phospholipids

ApoA

ApoB48

Question 13

nascent chylomicron

Answer 13

a lot of triglycerides on the inside

two main apoproteins are ApoB48 and ApoA1

relatively big 100nm to 1um in diameter

Question 14

How does a nascent chylomicron become a chylomicron?

Answer 14

ApoC and ApoE are added on with the help of HDL

Question 15

How are chylomicrons turned into chylomicron remnants?

Answer 15

lipoprotein lipase converts triglycerides to free fatty acids with the help of lipoprotein lipase with the help of ApoC

the triglycerides can pass through the cell membrane

Question 16

What happens to chylomicron remnants?

Answer 16

taken up by LRP in the liver and recycled

Question 17

endogenous pathway

Answer 17

represents liver production of VLDL, which undergoes metabolism very similar to chylomicrons

LDL is a product of this pathway

it may be taken up by LDL receptors in the liver

an important derivative is oxidized LDL which may be taken up by macrophages through a variety of receptors and is critical to driving the foam cell phenotype and therefore atherosclerosis progression

Question 18

What comprises a nascent VLDL?

Answer 18

ApoE, ApoB100, ApoC, cholesterol, and other lipids

Question 19

How does nascent VLDL become VLDL?

Answer 19

it matures after interactions with HDL

Question 20

How does VLDL become IDL?

Answer 20

VLDL acts as a cofactor for lipoprotein lipase due to the ApoC, which is lost during the reaction, giving rise to IDL

Question 21

How does IDL become LDL?

Answer 21

IDL interacts with HDL and becomes LDL, which only has ApoB100

the LDL is then taken up by LDLR in the liver and peripheral cells

Question 22

reverse cholesterol transport

Answer 22

the uptake f cholesterol by HDL from peripheral sites and delivery to the liver

an important pathway where excess cholesterol is disposed from the body

Question 23

Describe the process of Apo-A1 becoming HDL3

Answer 23

Apo-A1 is produced by the liver or intestine, and it is lipidated to form a discoidal form of HDL called pre-beta-HDL

pre-beta-HDL is then matured into HDL3 by lecithin-cholesterol acyltranferase, which is an enzyme that transfers an acyl group to cholesterol, forming cholesteryl ester

Question 24

Describe the fates of HDL3

Answer 24

matured into HDL2 through exchange with chylomicrons, VLDL

from there, it can be delivered directly to the liver

it can transfer cholesterol and cholesteryl ester to LDL, which is then delivered directly to the liver and taken up through the LDL receptor

Question 25

enterohepatic circulation

Answer 25

the recirculation of bile salts in the gut

important metabolite of choesterol and serve to solubilize fats so that they can be taken up by enterocytes

Question 26

genetic disorders of lipoprotein metabolism

Answer 26

familial hypercholesterolemia

PCSK9 deficiency

familial chylomicronemia syndrome (Fredickson Type I hyperlipoproteinemia)

Question 27

Fredrickson Classification

Answer 27

systemt hat classifies hyperlipoproteinemias into six subtypes based on serum lipid values and clinical features

Question 28

familial hypercholesterolemia

Answer 28

mutation in LDLR

autosomal dominant

1/500 are heterozygotes, who have cholesterol levels of around 300mg/dl

homozygotes have up to 1000 mg/dl

the hallmark of this disease is premature atherosclerosis

Question 29

symptoms of familial hypercholesterolemia

Answer 29

arcus corneae (deposition of cholesterol in the cornea)

tendonous xanthomas (thickened tendons)

eyelid xanthomas

premature atherosclerosis

Question 30

PCSK9 deficiency

Answer 30

a deficiency of the gene product of PCSK9 (proprotein convertase subtilisin/kexin type 9)

This protein binds to LDL Receptor and mediates its degradation

Patients who are deficient in PCSK9 therefore have elevated levels of LDL Receptor and—in turn—reduced levels of LDL-cholesterol

reduced risk of coronary artery disease

gain of function PCSK9 mutations exist, leading to increased LDL-C

Question 31

Familial Chylomicronemia Syndrome (Fredrickson Type I Hyperlipoproteinemia)

Answer 31

a syndrome of very high levels of chylomicrons, which manifests on laboratory testing as very high triglyceride levels

The underlying genetic defects are either a deficiency of lipoprotein lipase or ApoC-II, both of which are essential for hydrolysis of triglycerides for delivery to peripheral tissues

Question 32

How are lipoproteins measured clinically?

Answer 32

measurement of LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), and triglycerides

basic parts of the fasting lipid panel

LDL cholesterol is the amount of cholesterol and cholesteryl ester (found in IDL, LDL, and chylomicron remnants)

triglycerides is a measurment of VLDL and chylomicrons

Question 33

Friedewald Equation

Answer 33

0.2*triglycerides (TG) + HDL-cholesterol (HDL-C) + LDL-cholesterol (LDL-C) = total cholesterol (TC)