Lipid Metabolism

Question 1

Chylomicrons contain mostly _______. Which apolipoprotein is found on their surface?

Answer 1

mostly triglycerides, apo-B48

Question 2

Apolipoproteins A-I and A-II are structural proteins of _____.

Answer 2

HDL

Question 3

After ingestion of fats, _________ enter lacteals –> lymph –> systemic circulation.

Answer 3

chylomicrons

Question 4

What happens to chylomicrons shortly after they get into the systemic circulation?

Answer 4

The apo-CII on their surface binds to LPL on muscle/adipose cells to hydrolyze TAGs –> FFAs to give to the cells; the chylomicron then becomes a chylomicron remnant, which is then taken up by the liver via an apo-E receptor.

Question 5

What are the two major pathways of triglyceride transport?

Answer 5

Intestinal pathway, hepatic pathway

Question 6

What is the composition of a VLDL? Which apolipoproteins are found on VLDLs?

Answer 6

Mostly TAGs, some cholesterol esters. Apo-B100, E, and C-II

Question 7

Which apolipoprotein is a cofactor for lipoprotein lipase?

Answer 7

C-II

Question 8

Which apoprotein binds to the chylomicron remnant receptor on hepatocytes?

Answer 8

Apo-E

Question 9

Synthesized in the ________ (an organ), VLDLs are released into the blood and deliver FFAs to cells via membrane bound ________ (an enzyme on cell plasma membranes), turning the VLDL into a(n) _______. What are the possible fates of this lipoprotein?

Answer 9

Synthesized in the liver, VLDLs deliver FFAs to cells via lipoprotein lipase. Once enough triglycerides have been given to cells such that TAGs = CEs in the lipoprotein, it becomes an IDL. The IDL can then be endocytosed by a hepatocyte via LDL-R and (B-100 binds to it) or it can give more triglycerides to hepatocytes via hepatic TAG lipase and become an LDL (mostly cholesterol).

Question 10

Name two primary diseases of hyperlipidemia.

Answer 10

1. Familial hypertriglyceridemia

2. Familial combined hyperlipidemia

Question 11

Describe the biochemical problem involved in familial hypertriglyceridemia.

Answer 11

For some reason, too many TAGs are made in the liver and packaged in to big-ass VLDLs.

Question 12

Describe the biochemical problem involved in combined familial hyperlipidemia.

Answer 12

Too many apo-Bs are made so the liver makes a bunch of VLDLs to put them on. Result is increased triglycerides AND cholesterol.

Question 13

What would be the consequence of a defective lipoprotein lipase?

Answer 13

Chylomicrons would be unable to give triglycerides to cells –> increased chylomicrons and triglycerides in the blood

Question 14

What would be the consequence of a defective apo-CII?

Answer 14

Same as a defective LPL, cuz CII binds to LPL so chylomicrons (and VLDLs) can give triglycerides to cells.

Question 15

Which apo-E allele type has the highest affinity for the remnant receptor? What is the consequence of being an E2/E2 genotype?

Answer 15

E4 allele has highest affinity. E2 allele has the lowest, so E2/E2 genotypes have impaired remnant uptake –> increased remnants in plasma and low LDL levels. Hyperlipidemia (remnant removal disease) occurs in these people if another defect is added (inherited or acquired).

Question 16

Which lipids are elevated in remnant removal disease? What interesting physical exam finding might a patient have?

Answer 16

Both cholesterol and triglycerides are elevated because VLDLs and chylomicron remnants will be elevated due to an apo-E defect. Therefore, both cholesterol and triglycerides are elevated.

Question 17

What would you expect of a lipid profile in a patient with familial hypertriglyceridemia? What about familial combined hyperlipidemia?

Answer 17

Hypertriglyceridemia: for some reason too many triglycerides are put into VLDLs –> triglyceridemia only.

Familial combined hyperlipidemia: overproduction of apo-B –> overproduction of VLDLs that contain both TAGs and cholesterol esters –> increased levels of triglycerides AND cholesterol.

Question 18

What effect does insulin resistance have on lipoprotein lipase?

Answer 18

Insulin resistance impairs the action of LPL

Question 19

What type of lipid disorders are eruptive xanthomas associated with?

Answer 19

Hypertriglyceridemia seen in chylomicronemia, familial hypertriglyceridemia, or a combo of one of these plus diabetes.

Question 20

Highly elevated cholesterol levels are associated with what skin findings?

Answer 20

Tendon xanthomas - often seen in the achilles tendon and extensor tendons of the hand.

Question 21

What is the molecular defect involved in familial hypercholesterolemia?

Answer 21

Defective LDL receptor

Question 22

What is the mechanism of action of PCSK9 inhibitors?

Answer 22

These increase the half-life of LDL receptors –> increased LDL uptake.

Question 23

What is the inheritance pattern of familial hypercholesterolemia?

Answer 23

Autosomal dominant

Question 24

What is the mechanism of action of PCSK9 inhibitors?

Answer 24

Inhibit PCSK9 –> more LDL receptors –> more uptake of LDL

Question 25

Name a PCSK9 inhibitor.

Answer 25

Evolocumab

Question 26

What is the mechanism of action of gemfibrozil?

Answer 26

PPAR-alpha agonist –> increased LPL activity –> decreased TGs and mildly decreased LDL