Lipoprotein Physiology I

Question 1

­- cholesterol (particularly ­ LDL) leads
to atherosclerosis and is a modifiable
risk factor for cardiovascular disease (a
leading cause of death in Canada

• ­ triglyceride linked to ___
  (which itself can be fatal) and
  associated with cardiovascular
  disease

Answer 1

­- cholesterol (particularly ­ LDL) leads
to atherosclerosis and is a modifiable
risk factor for cardiovascular disease (a
leading cause of death in Canada

• ­ triglyceride linked to pancreatitis
  (which itself can be fatal) and
  associated with cardiovascular
  disease

Question 2

… it makes up most of
adipose tissue and mostly comes
from diet in the Western world

Answer 2

TRIGLYCERIDE: Composed of
glycerol backbone with ester
linkages to 3 fatty acids

Question 3

a non-nutritive lipid that is
nonetheless essential for life… needed for cell membrane fluidity, for steroidogenesis

Answer 3

cholesterol

Question 4

Lipids are water insoluble and cannot freely move around the circulation. Rather, lipids are carried by specific particles, called ___, which transport them throughout the body. The outer layer is composed of ___ with cholesterol and ___. The core is made up of ___ and cholesteryl esters.

Answer 4

Lipids are water insoluble and cannot freely move around the circulation. Rather, lipids are carried by specific particles, called lipoproteins, which transport them throughout the body. The outer layer is composed of phospholipids with cholesterol and apolipoproteins. The core is made up of TG and cholesteryl esters.

Question 5

3 functions of apolipoproteins

Answer 5

1. direct lipoprotein particles to the appropriate target sites by acting as ligands for receptors (apoB100 for LDL receptor)
2. Co-factor for enzymes for metabolism
3. maintain structure of lipoproteins for lipid shuttling.

Question 6

list the types of lipoproteins from biggest/least dense to smallest/most dense

Answer 6

1. CM
2. CM remnant

VLDL

IDL

LDL

HDL

Question 7

3 lipoprotein pathways

Answer 7

1. exogenous lipid transport (what happens after we eat)
2. endogenous lipid transport (how lipids are mobilized from the liver to the peripheral sites)
3. reverse cholesterol transport (how we get rid of choelsterol).

Question 8

Exogenous pathway: how we transport lipids from our food to our liver. Outline the pathway

Answer 8

1. we eat fat– lipids account for 30-40% of daily calories with typical north american diet.
2. dietary TGs are broken down into FAs and MG by PANCREATIC LIPASE.
3. Lipids (FA, MG, and cholesterol) are then packaged into bile salt micells and absorbed by duodenal enterocytes. Cholesterol is taken up by NPC1L1

4. after absorption, FAs and MGs are resynthesized into TGs in the cell, and lipids are then packaged to form CMs– enzyme MTP facilitates this process

5. CMs are secreted into the mesenteric lymphatics and enter the circulation by thoracic duct.
6. LPL enzyme with APOCII co factor hydrolyzes TGs in the CMs (freeing FAs for peripheral tissue)– CM remnants remain.
7. CM remnants are removed by the liver via LRP1 and LDL receptor(which recognize apoE)

Question 9

exogenous pathway:

1. we eat fat– lipids account for 30-40% of daily calories with typical north american diet.
2. dietary TGs are broken down into FAs and MG by _____.
3. Lipids (FA, MG, and cholesterol) are then packaged into __ __ micells and absorbed by duodenal enterocytes. Cholesterol is taken up by __
4. after absorption, FAs and MGs are resynthesized into TGs in the cell, and lipids are then packaged to form ___– enzyme ___ facilitates this process
5. CMs are secreted into the ______cs and enter the circulation by thoracic duct.
6. __ enzyme with __ co factor hydrolyzes TGs in the CMs (freeing FAs for peripheral tissue)– CM __ remain.
7. CM remnants are removed by the liver via
   * *__** and __ receptor(which recognize __ as a cofactor)

Answer 9

1. we eat fat– lipids account for 30-40% of daily calories with typical north american diet.
2. dietary TGs are broken down into FAs and MG by PANCREATIC LIPASE.
3. Lipids (FA, MG, and cholesterol) are then packaged into bile salt micells and absorbed by duodenal enterocytes. Cholesterol is taken up by NPC1L1
4. after absorption, FAs and MGs are resynthesized into TGs in the cell, and lipids are then packaged to form CMs-- enzyme MTP facilitates this process
5. CMs are secreted into the mesenteric lymphatics and enter the circulation by thoracic duct.
6. LPL enzyme with APOCII co factor hydrolyzes TGs in the CMs (freeing FAs for peripheral tissue)– CM remnants remain.
7. CM remnants are removed by the liver via LRP1 and LDL receptor(which recognize apoE) on the liver surface

Question 10

orlistat moa

Answer 10

medications that inhibits pancreatic lipase and therefore causes fat malabsorption. it is marketed for the treatment of obesity, but is
rarely used because of its side-effects: bloating
and steatorrhea (oily stools)

Question 11

ezetimibe is a medication that inhibits NPC1L1. How does this affect lipid metabolism?

Answer 11

NPC1L1 are located on the duodenal enterocytes, allowing for cholesterol to move into the cells. without this, cholesterol will stay in the lumen of the gut and thus this medication is a cholesterol-lowering drug

Question 12

LPL deficiency and apoCII deficiency are
both diseases that result in ­­­ ____ TGs

Answer 12

in HIGHTER TG levels. Because Cms. cannot be metabolized and build up in the circulation. Recall that LPL and ApoCII are transporter enzymes that hydrozlye CMs in the lymph, freeing FAs for energy and creating CM remnants.

Question 13

apoE mutations result in ­ ___ TGs & ­ ___cholesterol

Answer 13

INCREAESED TGs and Cholesterol. ApoE work with LRP and LDL to bring CM remnants from the lymph to the liver. If you don’t have this cofactor, CM remnants cannot be cleared– causes DYSBETALIPOPROTEINEMIA

Question 14

which receptorsand co factor dysregulation causes dysbetalipoproteinemia?

Answer 14

apoE mutations, LRP or LDL receptor mutations. these are required to bring CM remnants from the lymph to the liver. If you don’t have this cofactor, CM remnants cannot be cleared– causes DYSBETALIPOPROTEINEMIA?

Question 15

Endogenous pathway: how lipids are mobilized from the liver to peripheral sites. Outline the pathway

Answer 15

1. lipids from the liver is mobilized
   - TG synthesis is mostly regulated by circulating fatty acids.
   - cholesteorl synthesis is dependent on HMG coA reductase enzyme with negative feedback from increased cholesterol.
   - liver then exports lipids (TG and cholesterol) by assembling VLDL
2. VLDL metabolsim
   - vldl is slowly cleared.

- LPL hydrolyzes TGs (freeing FAs for peripheral tissue)– IDL particles are ceated.

3. IDL metabolism– two fates
   - around 1/2 removed by liver via LDL receptor (which recognizes ApoE)
   - remaining 1/2 is converted to LDL by hepatic lipase (which removes TG)
4. LDL metabolsim: LDL is very slowly cleared. it is persistent in the body which is why they make up atherosclerotic plaques. LDL is taken up slowly by various cells around the body through the LDL receptor, which requires a APOB100 cofactor.
   - when LDL attaches to the LDL receptor, it forms a complex. Another protein, PCKS9 holds them together so that both the LDL particle and LDLR can be engulfed by the cell and broken down into cholesterol, amino acids and fatty acids together.

Question 16

Endogenous Pathway:

1. lipids from the liver is mobilized
   - TG synthesis is mostly regulated by circulating __ __.
   - cholesteorl synthesis is dependent on __ __ __ enzyme with negative feedback from increased __.
   - liver then exports lipids (TG and cholesterol) by assembling __
2. VLDL metabolsim
   - vldl is slowly cleared.
   - ___ hydrolyzes TGs (freeing FAs for peripheral tissue)– __ particles are ceated.
3. IDL metabolism– two fates
   - around 1/2 removed by liver via __ receptor (which recognizes __)
   - remaining 1/2 is converted to __ by __ __ (which removes TG)
4. LDL metabolsim: LDL is very slowly cleared. it is persistent in the body which is why they make up atherosclerotic plaques. LDL is taken up slowly by various cells around the body through the __ receptor, which requires a __ cofactor.
   - when LDL attaches to the LDL receptor, it forms a complex. Another protein, __ holds them together so that both the LDL particle and LDLR can be engulfed by the cell and broken down into cholesterol, amino acids and fatty acids together.

Answer 16

1. lipids from the liver is mobilized
   - TG synthesis is mostly regulated by circulating fatty acids.
   - cholesteorl synthesis is dependent on HMG coA reductase enzyme with negative feedback from increased cholesterol.
   - liver then exports lipids (TG and cholesterol) by assembling VLDL
2. VLDL metabolsim
   - vldl is slowly cleared.
   - LPL hydrolyzes TGs (freeing FAs for peripheral tissue)– IDL particles are ceated.
3. IDL metabolism– two fates
   - around 1/2 removed by liver via LDL receptor (which recognizes ApoE)
   - remaining 1/2 is converted to LDL by hepatic lipase (which removes TG)
4. LDL metabolsim: LDL is very slowly cleared. it is persistent in the body which is why they make up atherosclerotic plaques. LDL is taken up slowly by various cells around the body through the LDL receptor, which requires a APOB100 cofactor.
   - when LDL attaches to the LDL receptor, it forms a complex. Another protein, PCKS9 holds them together so that both the LDL particle and LDLR can be engulfed by the cell and broken down into cholesterol, amino acids and fatty acids together.

Question 17

LDL receptor mutations result in elevated ___ because of ___ LDL, a condition called:

Answer 17

elevated cholesterol from elevated LDL (type of cholesterol), a condition called famililla hypercholesterolemia

Question 18

3rd pathway: Reverse cholesterol transport. cholesterol cannot be metabolized by the
body & must be excreted by the liver to
maintain homeostasis (reverse cholesterol
transport)… this is accomplished by HDL. What are the steps?

Answer 18

1. forming HDL assembled in the plasma
2. HDL maturation
   - free cholesterol from peripheral cells are invorportated into the nascent HDL, producing a spherical HDL3. more and more free cholestrol from peripheral cells are secreted into the plasma where they are attached to HDL to create HDL2 and HDL1.
   - HDL grabs onto cholesterol to form HDL 3–>2–> 1 via cholesterol efflux, where cholesterol is transferred and esterfied to the HDL particle by LCAT enzyme.
3. mature HDL(2) metabolism– two fates
4. indirectly deliver cholesterol to liver by transferring cholesterols to VLDL, IDL, and CM remnants first via CETP enzyme (cholesterol is then handled by the endogenous pathway)
5. directly deliver cholesterol to liver for excretion

Question 19

reverse cholesterol tranport: HDL grabs onto cholesterol to form HDL 3–>2–> 1 via cholesterol efflux, where cholesterol is transferred and esterfied to the HDL particle by __ enzyme.

Answer 19

LCAT enzyme