Biochemistry of Lipids and Lipoproteins

Question 1

Describe the process of bring choelsterol to the liver

Answer 1

1. cholesterol is eaten in fats as TGs and is emulsified by bile salts
2. TGS are broken down by intestinal lipases to FFAs and glycerol FFAs and TG are absorbed through the intestinal lumen and then converted back into TGs
3. TGs are packaged into chylomicrons (with apolipoproteins and phospholipids)
4. Chylomicrons are transported through lymph and blood to liver
5. Lipoprotein lipase is activated by ApoCII and breaks down TGs into FFAs and glycerol so it cn be absorbed into the liver

Question 2

What is the function of NPC1L1

Answer 2

absorbs cholesterol and plant sterols from the intestine

**blocked by Ezitimibe**

Question 3

What is ABCG5/ABCG8? what disease is associated?

Answer 3

transporter that pushes plants back into the intestinal lumen

associated with sisterolemia which is a mutation in the transporter so you get a build up of plant sterols (tendon and subcutaneous xanthomas and risk of premature CHD)

Question 4

what happens after chylomicrons drop off their contents (TGs)? What apo is required? what apo is degraded?

Answer 4

chylomicron remnants are removed from circulation via LDL receptor or LDL lreceptor related protein (LRP)

this requires apoE

apoB-48 is degraded (bc this is the chylomicron transport one)

Question 5

what is dysbetalipoproteinemia?

Answer 5

type III hyperlipoproteinemia

absence of ApoE so you can’t remove remnants of chylomicron so you have TG rich chylomicron remnants increased in plasma

Question 6

WHere is VLDL produced? what is the primary lipoprotein? what is the function ?

Answer 6

next smallest after chylomicrons. made in the liver with TG

apoB-100

transport TG and cholesteryl esters made in liver to tissues

Question 7

WHat is MTP and what disease is associated with

Answer 7

MTP transfers TG into the core of VLDL (and chylomicrons)

abetalipoproteinemia (you dont have any lipoproteins bc you can’t put TG in them so you cant make them)

Question 8

What is ACAT?

Answer 8

esterifies cholesterol to make CE that is found inside lipoproteins (Chylomicrons, VLDL, LDL)

Question 9

What happend after VLDL transports TG to adipose tissue and muscle?

Answer 9

lipoprotein lipase is actiavtes by ApoCII and the FFAs are removed from VLDL

FFAs are turned back to TGs and stored in adipocytes as lipid droplets or TGs are used for energy in muscles.

Now you have IDL which is taken up by LDL receptor or LDL

Question 10

What is the function of LDL? wat is plasma clearance mediated by

Answer 10

to transport CE to peripheral tissues and HDL-derived CE back to the liver

plasma clearance is mediated by apo100 and best way to influence plasma clearance is via modulation of genes for LDL receptor

Question 11

why are LDLs more likely to become oxidized and then be involved in atheromas than VLDLs or chylomicrons

Answer 11

their half life is days and the others are less than an hour. so there is just more time to get oxidized!

Question 12

what does PCSK9 do? why is this important

Answer 12

prevents recycling of LDLR

there are gain of function mutations in this where you can;t pull LDL from plasma and have too much LDL in plasma

there are loss of function mutations where you pull a TON of LDL from plasma :)

there are drugs that block PCSK9 (aricumab-injectable)

Question 13

What happens if you don’t have ApoAI?

Answer 13

You can’t make HDL

Question 14

What is ABCA1? WHat disease is associated with mutations in ABCA1?

What is the difference between ABCA1 and ABCG1?

Answer 14

• helps release free cholesterol to apoA1 to make discoidal (oreo cookie) HDL, but not sperical HDL
• Tagier disease=mutations in ABCA1 make it so you dont really have HDL
  
  • homozygous- low low HDL, enlarge orange tonsils
  • heterozygous-half of normal HDL-C levels
• APBCG1 promotes cholesterol efflux to mature sperical HDL instead ot ApoA1

Question 15

WHat does LCAT do? WHat disease is associated with deficiency?

Answer 15

• helps form the CE core of HDL
• turns discoidal immature HDL into spherical mature HDL by filling it with esterified cholesterol
• discoidal HDL take non-esterified cholesterol from macrophages. LCAT takes that non-esterified HDL and esterifies it so that it can be in the core of the discoidal HDL. once the discoidal HDL has esterified HDL in its core it is a sperical mature HDL
• FIsh eye disease
  
  • homo: corneal clouding, nephropathy, hemolytic anemia, HDL deficiency
  • hetero: Half of normal HDL levels

Question 16

What does CETP do? is it good or bad?

Answer 16

exchanges lipids between LDL and HDL

It allows LDL to give HDL some choelsterol (CE) in exchange for TG

Bad! deficiency in CETP reduces risk of heart disease

Question 17

What does Hepatic Lipase do? (HL)

Answer 17

• Hydrolyzes smaller, spherical HDL that recirculates and aquires additional free cholesterol from tissues
• HL is associated with low HDL levels bc is HDL gets small enough it just goes to the kidney to be destroyed
  *

Question 18

What is SR-B1?

Answer 18

• The HDL receptor
• overexpression of SR-B1 leads to increased uptake of HDL-CE meaning decreased HDL-cholesterol so cholesterol levels go down
• HDL uptake is “selective uptake” where only the CE core of the HDL is transferred so the HDL can go out into the circulation and get more Cholesterol

Question 19

how do covalent modifications provide regulation of cholesterol?

Answer 19

• HMG-CoA get phosphorylated and this decreases its activity in making cholesterol
• AMP activates a kinase which phosphorylates HMG-CoA
• It is also phosphorylated by glucagon and epinephrine
• But is depohosphorylated by insulin
• leads to **short term regulation**

Question 20

What is the mechanism for feedback regulation of cholesterol synthesis? **exaplain what would happen if you didn’t need more cholesterol

Answer 20

Decrease HMG CoA Reductase

Increase ACAT so more cholesterol is esterified for storage(bc lipoproteins are for storing and transporting cholesterol)

decreases LDL receptor transcription, bc we don’t want to take in more cholesterol from the plasma

if you need more cholesterol you would increase HMG-CoA Reducatase, decrease ACAT so that you don’t store your cholesterol and increase LDL receptors so you bring more cholesterol into the cell (hepatocyte usually)

Question 21

What are scavenger receptors?

Answer 21

They are on macrophages

once LDL is oxidized, it is recognized by the scavenger receptors. Scavenger receptors are not regulated by cellular cholesterol levels like the rest of the body. This leads to macrophages uptaking the oxidized LDL creating a foam cell (CE accumulation). Foam cells accumulate and become a fatty streak, then a plaque! (atherosclerosis)