Lipoprotein Metabolism Flashcards Preview

Cardiovascular > Lipoprotein Metabolism > Flashcards

Flashcards in Lipoprotein Metabolism Deck (33):
1

sphingomyelin

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

2

cholesterol

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

3

HMG-CoA reductase

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

4

main classes of lipids

fatty acids

triglycerides

phospholipids

cholesterol

5

typical lipoprotein structure

apolipoproteins

amphipathic surface - mostly phospholipids and cholesterol

hydrophobic core - triglycerides and choleteryl ester

6

purpose of lipoproteins

deliver fats as fuel

cholesterol transport

phospholipid transport

7

roles of apolipoproteins

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

8

major lipoprotein classes

chylomicrons

chylomicron remnants

very low density lipoproteins (VLDL)

intermediate density lipoproteins (IDL)

low density lipoproteins (LDL)

and high density lipoproteins (HDL)

9

key pathways of lipoprotein transport

exogenous pathway

endogenous pathway

reverse cholesterol transport

enterohepatic circulation

10

key enzymes of lipoprotein transport

lipoprotein lipase (LPL)

lecithin-cholesterol acyltransferase (LCAT)

cholesteryl ester transfer protein (CETP)

11

exogenous pathway

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

12

enterocyte package

triglycerides

cholesterol

phospholipids

ApoA

ApoB48

13

nascent chylomicron

a lot of triglycerides on the inside

two main apoproteins are ApoB48 and ApoA1

relatively big 100nm to 1um in diameter

14

How does a nascent chylomicron become a chylomicron?

ApoC and ApoE are added on with the help of HDL

15

How are chylomicrons turned into chylomicron remnants?

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

16

What happens to chylomicron remnants?

taken up by LRP in the liver and recycled

17

endogenous pathway

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

18

What comprises a nascent VLDL?

ApoE, ApoB100, ApoC, cholesterol, and other lipids

19

How does nascent VLDL become VLDL?

it matures after interactions with HDL

20

How does VLDL become IDL?

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

21

How does IDL become LDL?

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

22

reverse cholesterol transport

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

23

Describe the process of Apo-A1 becoming HDL3

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

24

Describe the fates of HDL3

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

25

enterohepatic circulation

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

26

genetic disorders of lipoprotein metabolism

familial hypercholesterolemia

PCSK9 deficiency

familial chylomicronemia syndrome (Fredickson Type I hyperlipoproteinemia)

27

Fredrickson Classification

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

28

familial hypercholesterolemia

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

29

symptoms of familial hypercholesterolemia

arcus corneae (deposition of cholesterol in the cornea)

tendonous xanthomas (thickened tendons)

eyelid xanthomas

premature atherosclerosis

30

PCSK9 deficiency

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

31

Familial Chylomicronemia Syndrome (Fredrickson Type I Hyperlipoproteinemia)

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

32

How are lipoproteins measured clinically?

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

33

Friedewald Equation

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