Lipoprotein Physiology

Question 1

Relative polarities of cholesterol ester, triglyceride, unesterified cholesterol and phospholipids

Answer 1

• un-esterified cholesterol (aka “cholesterol) & phospholipids = more polar
• triglycerides + cholesterol esters = less polar

Question 2

Characteristics of lipoproteins (general)

Answer 2

• named based on density
• more triglyceride ==> less dense
• descriptors: size, associated apo-lipoproteins, and composition (triglyceride vs. cholesterol)
• 5 classes

Question 3

Classes of lipoproteins

Answer 3

• chylomicrons
• very low density lipoproteins (VLDL)
• remnant particles & intermediate density lipoproteins (IDL)
• low density lipoproteins (LDL)
• high density lipoproteins (HDL)

Question 4

Characteristics of chylomicrons

Answer 4

• made by the GI tract from dietary fat
• physically large and have far more triglyceride than cholesterol (>10:1)
• This class of particle is responsible for the observed rise in triglyceride levels following a meal.

Question 5

Characteristics of VLDLs

Answer 5

• relatively large particles that are triglyceride rich (tg:chol = 5:1) and are made by the liver
• source of “basal triglyceride production”
• They deliver triglyceride to peripheral tissues between meals, but are also made at lower levels in the post-meal period

Question 6

Characterstics of IDLs

Answer 6

• metabolic byproducts of the metabolism of chylomicrons and VLDL.
• As the triglyceride rich lipoproteins deliver tg to peripheral tissues they become physically smaller and “relatively” cholesterol enriched.
• These particles are mid-sized and have roughly equal amounts of triglyceride and cholesterol.
• They are atherogenic.

Question 7

Characteristics of LDLs

Answer 7

• produced from the metabolism of VLDL.
• They have more cholesterol than tg, and are quite atherogenic.
• The less tg they contain the smaller and more dense they are.
• Small dense LDL are especially atherogenic.
• They are cleared from the circulation by the liver.

Question 8

Characteristics of HDLs

Answer 8

• They collect cholesterol from peripheral tissues and transport it back to the liver.
• They also provide a reservoir of phospholipids for other lipoprotein particles, and they can exchange triglyceride and apo-proteins with other particles in the circulation.
• HDL cholesterol levels are inversely correlated with atherosclerotic risk presumably through their role in the process of reverse cholesterol transport

Question 9

Chylomicron pathway

Answer 9

• lipids then diffuse or are transported across the intestinal wall ==> triglycerides are re-synthesized and packaged into chylomicron particles that contain apoprotein B48.
• chylomicrons ==> gut lymphatics ==> central circulation where they acquire apoproteins C-2 and E from HDL particles
• triglyceride in chylomicrons is broken down by lipoprotein lipase (LPL) at the endothelial surface of tissues such as muscle and adipose tissue
• chylomicron-remnant particles that are taken up by the liver

Question 10

Chylomicron contents/purpose

Answer 10

• chylomicrons handles lipids that enter the body through the diet
• majority of the lipid in the chylomicron is triglyceride

Question 11

VLDL contents/purpose

Answer 11

• triglyceride rich lipoprotein synthesized by the liver
• remainder of its mass made up of phospholipid and protein
• VLDL particles contain one apoprotein B molecule per particle that remains with it throughout its metabolism = B100
  
  • B48 = truncated version of B100

Question 12

VLDL pathway

Answer 12

• Following secretion by the liver VLDL acquire apoprotein C-2 and apo-lipoprotein E from HDL in the peripheral circulation
• VLDL metabolized by LPL ==> VLDL-remnant particles ==> low density lipoproteins (LDL)
• LDL particles are cleared from the blood by the LDL receptor.
  
  • most LDL particles are cleared by the liver.
  • Cholesterol taken up by the LDL receptor at the liver is internalized and regulates hepatic cholesterol synthesis and metabolism

Question 13

LDL contents/purpose

Answer 13

• VLDL - most of triglyceride ==> LDL particles contain ~10% triglyceride, and ~45% cholesterol.
• LDL particles are the major cholesterol carrier in the plasma.
• LDL particles still contain apo B100.

Question 14

HDL contents/purpose

Answer 14

• high density lipoproteins (HDL) functions in part to bring cholesterol (and to a lesser extent triglyceride) from the periphery back to the liver in what has been called “reverse cholesterol transport”.
• Nascent HDL containing the main structural apo-protein apo A1
  
  • synthesized by the liver and intestine
  • circulates in plasma and picks up free cholesterol from peripheral tissues via diffusion and facilitated transport via the ABC-A1 cassette.

Question 15

Mechanism of HDL pathway

Answer 15

• Nascent HDL circulates at periphery
• traps free cholesterol by converting to less polar cholesterol ester w/lecithin cholesterol acyltransferase (LCAT)
• HDL matures ==> HDL₃ transfers cholesterol esters to VLDL in exchange for triglycerides w/cholesterol exter transfer protein (CETP)
• HDL₃ ==> HDL₂ ==> liver

Question 16

Fxn of ABC A1

Answer 16

• ATP binding cassette (ABC) transporters appear to be very important in the transport of cholesterol from peripheral tissues to apo A-1, the core apoprotein of HDL
• no ABC A1 ==> very low levels of HDL cholesterol ==> premature atherosclerosis

Question 17

Fxn of LCAT

Answer 17

• catalyses the transfer of a fatty acids from the phospholipid lecithin to un-esterified cholesterol.
• ==> cholesterol ester which is very non-polar and which is then more tightly bound to the HDL particle ==> more effectively transported back to the liver
• Lack of LCAT ==> low HDL ==> renal failure, corneal opacities

Question 18

Fxn of CETP

Answer 18

• Cholesterol ester transfer protein (CETP) is a protein that catalyzes the exchange of the non-polar lipids
  
  • cholesterol esters (CE) and triglycerides (tg) between lipoprotein particles of different classe
• CE from HDL is exchanged for tg present in VLDL and remnants.
• alternative route of clearance for triglyceride

Question 19

Major fxns of apolipoproteins + examples

Answer 19

• structural background of lipoprotein particle
  
  • apoB₄₈ (chylomicrons)
  • apoB₁₀₀ (VLDL & LDL)
  • apo A1 (HDL)
• enzymatic cofactors
  
  • apoC2 = cofactor for LPL
• ligands for receptors
  
  • apoB₁₀₀ = ligand for LDL receptor
  • apo E = ligand for remnant receptor
• unknown; assoc. w/atherosclerosis
  
  • apo(a)