18: Lipoproteins

Question 1

Cholesterol and its ester form are highly hydrophobic and are therefore transported in blood as a component of ________.

Answer 1

Cholesterol and its ester form are highly hydrophobic and are therefore transported in blood as a component of lipoproteins.

Question 2

Cholesterol is part of the _______ shell of lipoproteins, while the more hydrophobic cholesterol esters are found in the _____ of the particles.

Answer 2

Cholesterol is part of the outer shell of lipoproteins, while the more hydrophobic cholesterol esters are found in the core of the particles.

Question 3

Cholesterol synthesized in the liver is packaged with triglyceride and other components to form ______ which is released into the circulation.

Answer 3

Cholesterol synthesized in the liver is packaged with triglyceride and other components to form VLDL which is released into the circulation.

Question 4

In the circulation triglyceride is digested by ________ converting VLDL to ______ and then ______.

Answer 4

In the circulation triglyceride is digested by lipoprotein lipase converting VLDL to IDL and then LDL.

Question 5

IDL and LDL bind to receptors on the surface of _______ cells, are endocytosed and components are reutilized.

Answer 5

IDL and LDL bind to receptors on the surface of hepatic cells, are endocytosed and components are reutilized.

Question 6

______ transfers ApoE and ApoCII to nascent chylomicrons and VLDL.

Answer 6

HDL transfers ApoE and ApoCII to nascent chylomicrons and VLDL.

Question 7

HDL is involved with reverse transport of cholesterol from _______ to the _____ for reutilization.

Answer 7

HDL is involved with reverse transport of cholesterol from cell membranes to the liver for reutilization.

Question 8

Atherosclerotic plaques are associated with elevated blood _______. High ______ correlates with increased likelihood of atherosclerotic plaques. Elevated ______ is protective because of its reverse cholesterol transport activity.

Answer 8

Atherosclerotic plaques are associated with elevated blood cholesterol. High LDL correlates with increased likelihood of atherosclerotic plaques. Elevated HDL is protective because of its reverse cholesterol transport activity.

Question 9

Describe LDL & HDL

Answer 9

LDL (Bad) Cholesterol
When too much LDL (bad) cholesterol circulates in the blood, it can slowly build up in the inner walls of the arteries that feed the heart and brain. Together with other substances, it can form plaque, a thick, hard deposit that can narrow the arteries and make them less flexible. This condition is known as atherosclerosis. If a clot forms and blocks a narrowed artery, heart attack or stroke can result.

HDL (Good) Cholesterol
About one-fourth to one-third of blood cholesterol is carried by high-density lipoprotein (HDL). HDL cholesterol is known as “good” cholesterol, because high levels of HDL seem to protect against heart attack. Low levels of HDL (less than 40 mg/dL for men and less than 50 mg/dL for women) also increase the risk of heart disease.

Medical experts think that HDL tends to carry cholesterol away from the arteries and back to the liver, where it’s passed from the body. Some experts believe that HDL removes excess cholesterol from arterial plaque, slowing its buildup.

Question 10

What are lipoproteins?

Answer 10

The lipoprotein complexes include chylomicrons, VLDL, IDL, LDL, & HDL. Lipoprotein particles protect their hydrophobic cargo from the aqueous environment, while shuttling them from tissue to tissue. When lipid deposition occurs, this leads to plaque formation which causes atherosclerosis or narrowing of blood vessels.

The lipoproteins contain a hydrophobic core of TAG’s & cholesterol esters; however, they also have a shell containing amphipathic phospholipids. TAG’s & cholesterol carried by lipoproteins are obtained either from the diet = exogenous source or de novo synthesis = endogenous source.

Lipoprotein particles can be separated based on their electrophoretic mobility or based on their density by ultracentrifugation.

Lipoproteins have a variety of functions including providing recognition sites for cell surface receptors, activators for enzymes in lipoprotein metabolism, structural components of lipoprotein, others are transferred between lipoproteins.

Question 11

Rank the blood lipoproteins from least to most dense & from largest to smallest:

Answer 11

Rank the blood lipoproteins from least to most dense & from largest to smallest: Chylomicrons, VLDL, LDL, HDL.

Chylomycrons are largest & least dense

HDL = most dense & smallest

Ratio = Protein/ Lipid

HDL has the least fat & fat is bad

Question 12

Discus ApoC-II & Apo E: where they are sunthesized & their functions.

Answer 12

ApoC-II is made in the liver, it is a lipoprotein lipase activator.

Apo E is made in the liver, & it is recognized by LDL & CM remnant LRP receptors.

Question 13

List the steps of Chylomicron metabolism

Answer 13

1. Chylomicron metabolism occurs after occurs after eating a meal (exogenous) & occurs in the intestinal mucosal cells. Apo B-48 is synthesized from Apo B-100 via post-transciptional editing. The Apo B-48 is then transferred from the ER to the Golgi & are packaged in secretory vesicles. These vesicles then fuse with the plasma membrane resleasing the ApoB-48 chylomicron which first enters the lymphatic system & then the blood.
2. In the blood, the nascent chylomicron gets Apo-E which will be recognized by hepatic receptors & Apo-C including Apo C-II from HDL particles.
3. Lipoprotein Lipase (LPL) is in the capillary walls of most tissues. It becomes activated by Apo C-II & hydrolyzes TAG’s in chylomicrons giving FA’s or glycerol. The FA are stored in adipose or used for energy by muscles & the glycerol is used by the liver for lipid synthesis or gluconeogenisis.
4. After being acted upon by LPL, the particle decreases in size & increases in density. Apo-C & Apo C-II are then returned to the HDL from which they came from & create what is called a chylomicron remnant.
5. The chylomicron remnant is then taken up by the liver via its Apo-E which binds to lipoprotein receptors on the liver. This is followed by endocytosis & then lysosomal hydrolytic enzymes degrade the chylomicron to cholesterol, amino acids, FA’s. The Apo E receptors are then recycled.

Question 14

Discuss lipoprotein lipase:

Answer 14

In the fed state with elevated insulin levels, adipose tissue LPL expression is increased & muscle LPL is decreased.

In the fasting state adipose tissue LPL expression is decreased & muscle LPL is increased.

Patients with a deficiency of either LPL or Apo C-II accumulate chylomicron TAG in the plasma & have an increased risk for pancreatitis.

Question 15

List the steps of VLDL metabolism:

Answer 15

VLDL is produced in the liver. They are secreted into the blood by the liver as nascent particles containing Apo B-100 ligand.

The VLDL then obtains Apo E & Apo C-II from HDL. Some TAG’s are transferred from VLDL to HDL in exchange for cholesterol esters in a rxn catalyzed by cholesteral ester exchange protein.

The function of VLDL is to carry lipids from the liver to peripheral tissues.

Lipoprotein Lipase (LPL) is in the capillary walls of most tissues. It becomes activated by Apo C-II & hydrolyzes TAG giving FA’s or glycerol. The FA are stored in adipose or used for energy by muscles & the glycerol is used by the liver for lipid synthesis or gluconeogenisis.

VLDL is converted to LDL in the blood with Intermediate density lipoproteins or IDL’s or VLDL remnants observed in the rxn.

Apo C-II & Apo-E are returned to the HDL particles. The LDL particle binds to a receptor on the surface of hepatocytes & extra-hepatic tissue.

IDL’s can also be taken up by hepatocytes through receptor mediated endocytosis that uses apo E as the ligand.

Question 16

Discuss the diseases of VLDL metabolism:

Answer 16

Nonalcoholic fatty liver = hepatic steatosis occurs when there is an imbalance between TAG synthesis & sectretion of VLDL.

Apo E hase 3 isoforms (E2, E3, E4). E3 is the most common & E2 is the least. Apo E-2 binds poorly to receptors. Patients who are homozygous for E2 are deficient in clearance of chylomicrons or IDL & have FAMILIAL TYPE III HYPERLIPOPROTEINEMIA + HYPERCHOLESTEROLEMIA & premature atherosclerosis.

E4 isoform gives suceptability & decreased age onset for Alzheimers.

Question 17

What is the function of cholesterol ester transfer protein CETP?

Answer 17

CETP catalyzes the exchange of TAG from VLDL with cholesterol ester ester from HDL. The higher the TAG or TG the higher the exchange rate.

This explains why high TAG containing lipoprotein particles in blood correlates with greater cholesterol return to liver via VLDL & IDL.

Question 18

Discuss LDL:

Answer 18

LDL particles contain less TAG than VLDL predecessors & more cholesterol than cholesterol esters.

The function of LDL is to provide cholesterol to the peripheral tissues & return it to the liver. LDL has ligand Apo B-100 & Apo E so these ligands bind to LDL receptors for these ligands in the peripheral tissues.

Question 19

List the steps of uptake & degradation of LDL (chylomicron & IDL) particles.

Answer 19

Note that similar mechanisms occur for the degradation of chylomicron remnants & IDL particles in the liver but their receptors only recognize Apo-E.

1. LDL receptors are glycosylated transmembrane proteins which are clustered in clathrin coated pits.
2. After LDL-LDL receptor binding, the LDL receptor complex is endocytosed with the assistance of clathrin forming the coated vesicle. A deficiency of LDL receptor causes elevated plasma LDL–patients with this have type 2 hyperlipidemia = familial hypercholesterolemia. Autosomal dominant FH is caused by increased activity of a protease that degrades the LDL receptor.
3. The coated vesicle then losses its clathrin coat & fuses with other vesicles to form endosomes.
4. The pH of the endosome drops based on ATP dependent proton pumping into the endosome. This uncouples the receptor from the LDL particle & they separate into distinct areas of what is called the compartment for uncoupling receptor & ligand or CURL.
5. The receptors are recycled to the plasma membrane & the endosome fuses with the lysosome. Lysosomal hydrolases degrade the LDL, chylomicron, or IDL particles releasing AAs, FAs, cholesterol, & phospolipids.
   * An oversupply of cholesterol to the liver can decrease the expression and increase the degredation of HMG CoA reductase (rate limiting in cholesterol synthesis). In a simmilar mechanism, oversupply of cholesterol can diminish the expression of liver LDL receptor. This coordinates the regulation of LDL receptor & rate limiting enzyme in cholesterol synthesis.

Question 20

What happens if cholesterol is not needed immediatly for synthetic or structural purposes?

Answer 20

If cholesterol is not needed immediatly for synthetic or structural purposes, it can be esterified by Acyl CoA: Cholesterol Acyltansferase (ACAT). The resulting cholesterol ester can be strored in the cell. ACAT activity is increased by the presence of an oversupply of intracellular cholesterol.

Question 21

Describe Familial Hypercholesterolemia

Answer 21

Familial hypercholesterolemia is a genetic disorder caused by a point mutation on chromosome 19 coding for the LDL receptor gene.

The defect makes the body unable to remove low density lipoprotein (LDL, or “bad”) cholesterol from the blood. This results in high levels of LDL in the blood. High levels of LDL cholesterol make you more likely to have narrowing of the arteries from atherosclerosis at an early age. Those with familial hypercholesterolemia are more likely to have a family history of high cholesterol and heart disease at a younger age than normal.

LDL cholesterol normally circulates in the body for 2.5 days, and subsequently binds to the LDL receptor on the liver cells, undergoes endocytosis, and is digested. LDL is removed, and synthesis of cholesterol by the liver is suppressed in the HMG-CoA reductase pathway.

In FH, LDL receptor function is reduced or absent, and LDL circulates for an average duration of 4.5 days, resulting in significantly increased level of LDL cholesterol in the blood with normal levels of other lipoproteins. In mutations of ApoB, reduced binding of LDL particles to the receptor causes the increased level of LDL cholesterol.

Question 22

Describe HDL & its functions:

Answer 22

HDLs are formed in blood by addition of lipids to Apo A-1 which is synthesized in the liver & intestine & is secreted into the blood.

HDL functions include:

Supplier of Apo C-II & Apo E

Take cholesterol up from the peripheral tissues & return it to the liver as cholesterol esters

Esterification of cholesterol

Reverse cholesterol transport

Question 23

Discuss the esterification of cholesterol

Answer 23

When HDL takes up cholesterol it is esterified by lecithin:cholesterol acyl transferase.

LCAT (lecithin:cholesterol acyl transferase) is activated by Apo A-I and transfers the FA from C2 of PC cholesterol which produces hydrophobic cholesterol ester (CE). Esterification maintaines the cholesterol gradient allowing further uptake of cholesterol from the peripheral tissues to HDL.As HDL picks up CE it converts nascent HDL to the cholesterol poor HDL3 & then to the CE rich HDL2 particle that carries CE to the liver. CETP exchanges CE from HD: to VLDL with concurrent exchange of TAG from VLDL to HDL. This relieves product inhibition of LCAT. As VLDLs are catabolized to LDL, the CE’s transferred by CETP are taken up by the LDL receptor.

Question 24

What is reverse cholesterol transport?

Answer 24

The transfer of cholesterol from peripheral cells to HDL, from HDL to liver for bile acid/salt synthesis is essential for cholesterol homeostasis. This gives the inverse relationship between plasma HDL concentration & atherosclerosis & the idea that HDL is a good cholesterol carrier.

The efflux of cholesterol from peripheral tissues is catalyzed by ABCA1. The uptake of cholesterol esters from the liver involved the SR-B1 that binds HDL on the surface of the hepatocyte & selectively takes up the cholesterol esters from the particle. Hepatic lipase which degrades the TAG & phospholipids also participates in the conversion of HDL2 to HDL3

Question 25

Discuss oxidized lipoproteins & plaque formation in an arterial wall.

Answer 25

Macrophages have scavenger receptor activity in scavenger receptor class A that binds ligands causing endocytosis of modified LDL that has undergone oxidative damage.

The macrophage consumes excess oxidized LDL & become foam cell.

Foam cells participate in plaque formation!

Question 26

Discuss the mechanisms of atherosclerotic plaques in cardiovascular disease

Answer 26

As the plaque within a blood vessel matures, a cap forms over its expanding roof, which partially occludes the vascular lumen.

Vascular smooth muscle cells migrate from the media to the subintimal space & secrete plaque matrix materials & metaloproteases that thin the fibrous cap.

The thinning of the cap continues until it ruptures & exposes the cap contents to procoagulants in the circulation. This leads to thrombus formation.

If the thrombus completely occludes the blood vessel lumen, then an acute MI can occur.

Question 27

Know how to manipulate the Friedewald formula:

LDL-C =

Answer 27

LDL-C = TC - [HDL + VLDL*(TG/5)]