19 - Cholesterol and Triglycerides

Question 1

What is the role of albumin?

Answer 1

• In the blood, free fatty acids bind to hydrophobic pockets the surface of albumin
• From albumin, free fatty acids are translo-cated across the plasma membranes into the cytosol where they are activated to fatty-acyl CoA

Question 2

How do chylomicrons form?

Answer 2

• Dietary fats (free fatty acids, monoacylglycerols and glycerol) and cholesterol are absorbed by the enterocytes
• The enterocytes re-synthesize triacylglycerols and pack them into chylomicrons for distri-bution through the body

Question 3

What is the function of chylomicrons?

Answer 3

• The function of chylomicrons is the distribution of dietary lipids from enterocytes to the rest of the body
• For transport of dietary lipids - When you consume fat from the diet, they are transported by chylomicrons

Question 4

What is the relationship between VLDL, IDL and LDL?

Answer 4

Very low density lipoproteins (VLDL), intermediate density lipo-proteins (IDL) and low density lipoproteins (LDL) are maturation stages of the same particle

Question 5

What is the function of VLDLs?

Answer 5

• VLDLs are used for the transport of endogenous lipids - Made in the liver, liver needs to transport lipids in the form of VLDLs
• VLDLs are synthesized by the liver to distribute endogenously synthesized lipids to peripheral tissues
• Similar to chylomicrons, VLDLs lose lipids and transform into IDLs and then LDLs

Question 6

How do VLDLs become IDLs and LDLs?

Answer 6

Not all of the VLDL remnants are immediately cleared from the blood - Some stay in circulation, lose more triglycerides and acquire more cholesteryl esters. The physical density of the particles increases, transforming them from very low density (VLDL) to intermediate density (IDL) and finally to low density (LDL) lipoproteins.

Question 7

What are HDLs?

Answer 7

• Vesicles for reverse lipid transport/excretion - These are particles that are made “empty” - As they circulate, they suck up lipids
• High density lipoproteins (HDL) function in reverse cholesterol transport from the peripheral tissues to the liver
• As the HDL particles circulate, they grow by acquiring triacyl-glycerols from other lipoproteins

Question 8

How do chylomicrons lose lipids?

Answer 8

Lipoprotein lipases on the surface of target cells cleave triacylglycerols and liberate free fatty acids from the chylomicrons

Question 9

How do VLDLs lose lipids?

Answer 9

Similar to the situation in chylomicrons, VLDLs gradually lose triacylglycerols from the core of the particle through the action of lipoprotein lipases.

Question 10

What are the different classes of apoproteins?

Answer 10

• Apoprotein A
• Apoprotein B
• Apoprotein C
• Apoprotein E

Question 11

What does apoprotein A do?

Answer 11

A = activates lecitin

Activators of lecitin: cholesterol acyltransferase (LCAT). Extract lipids from membranes for reverse transport
Activate an acetyltransferase, making cholesterol very hydrophobic, trapping it in the core – this means they regulate the ENTRY

Question 12

What does apoprotein B do?

Answer 12

B = building blocks

Structural proteins, interact with lipoprotein receptors and mediate the uptake of the particle into target cells.
Provide structural support for a variety of lipoproteins (scaffold)
If you have faulty apoprotein Bs, it will affect a variety of lipoprotein classes
Also interacts with the receptor
Regulate the EXIT

Question 13

What do apoprotein Cs do?

Answer 13

C = controllers

Modulate lipoprotein lipase (LPL/HTGL) activity, liberate free fatty acids and glycerol from lipoproteins.
Degrades lipids (make them less hydrophobic)
LPL cleaves the very hydrophobic lipids from the lipoprotein, so they are then allowed to leave the lipoprotein

Question 14

What do apoprotein Es do?

Answer 14

E = exit regulators

Bind to receptors to allow removal of remnant particles from the circulation.
Mediate the binding of the lipoprotein to the receptor
Triggers the removal of the lipoprotein from the circulation

Question 15

What types of tests are done to assess blood lipid profiles?

Answer 15

Total serum cholesterol
Fasting lipid profile
Ultracentrifugation

Question 16

Describe the total serum cholesterol test

Answer 16

Total serum cholesterol. Good approximation of serum LDL concentration. Not perfect but pretty good.

Question 17

Describe the fasting lipid profile test

Answer 17

No dietary lipids (chylomicrons)

Consists of measurements of total cholesterol, total glycerides and HDL cholesterol

Question 18

How do you determine LDL?

Answer 18

LDL is NOT measured, it is CALCULATED
LDL cholesterol is calculated with the Friedewald formula:
LDL (mg/dL) = Total cholesterol – HDL cholesterol – 20% of triglycerides ***
Need to be able to calculate this!

Question 19

Describe the ultracentrifugation test

Answer 19

Best way to look at what’s going
You will see how the particles separate – can use this for testing for a very rare lipid disorder or in an academic situation, not really used much in clinical practice

Question 20

Describe the basics of the Fredrickson classification

Answer 20

The most widely accepted standard, the Fredrickson classifica-tion, categorizes dyslipidemias based on the changes in blood lipid composition.
If the blood in the tube turns yellow/opaque it is bad.

Question 21

What primary dyslipidemias exist?

Answer 21

Elevated cholesterol, normal triglycerides
Familial hypercholesterolemia
Familial defective ApoB100

Elevated triglycerides
Familial combined hyperlipidemia
Familial dysbetalipoproteinemia

Question 22

Describe familial hypercholesterolemia

Answer 22

Familial Hypercholesterolemia (FH)(1/500)
results from defects in the ApoE/B (LDL) receptor
autosomal co-dominant trait
FH is classified as dyslipidemia IIa or IIb

Question 23

Describe familial defective ApoB100

Answer 23

Familial Defective ApoB100 (FDB) (1/10,000)

Similar to FH – defective ApoB100 prevents binding of LDL to receptor

Question 24

Describe familial combined hyperlipidemia

Answer 24

Familial Combined Hyperlipidemia (FCHL) (1/50)
Variable etiology; may result from overproduction of ApoB100
increased production of VLDL , abundance of VLDL, IDL, LDL

Question 25

Describe familial dysbetalipoproteinemia

Answer 25

Familial Dysbetalipoproteinemia (FDBL) (1/10,000)
Defective ApoE prevents uptake of remnants by liver
Increase in all ApoB-containing lipoproteins

Question 26

What are the secondary dyslipidemia?

Answer 26

Obesity
Diabetes
Liver diseases

Question 27

Describe the process of obesity causing a secondary dyslipidemia

Answer 27

High insulin (liver produces fatty acids from a lot of glucose)
Large amounts of adipose tissue with decreased insulin sensitivity (lots of fatty acids released, adipose tissue is not very insulin sensitive)
Liver produces large amounts of VLDL (high LDL cholesterol)

Question 28

Describe how diabetes leads to a secondary dyslipidemia

Answer 28

This does NOT apply to type I diabetes - there are NO abnormalities when patient is under good glycemic control

For type II diabetes…
Inactive lipoprotein lipase (VLDLs and chylomicrons increase)
Active hormone sensitive lipase (lots of fatty acids released)
Active fatty acid synthesis in the liver (VLDL increases)

Notes:
Free fatty acids will be circulating in Type II
They will be releasing free fatty acids all the time
The liver sees a lot of this
The liver deals with it by making an ester, then making a lot of VLDLs
Even if glucose is well controlled, you can still see a lot of this high fat and VLDLs

Question 29

What two liver diseases can cause a secondary dyslipidemia?

Answer 29

Liver failure (hepatitis)
Cholestasis

Question 30

Describe how liver failure can cause a dyslipidemia

Answer 30

Liver does not produce enough VLDLs and HDLs - abnormally low cholesterol and triglycerides will be seen

Question 31

Describe how cholestasis can cause a secondary dyslipidemia

Answer 31

Cholestasis, i.e. blockage of the gall duct, will cause an inability to excrete cholesterol and bile salts. When the path to cholesterol ex-cretion is blocked, free cholesterol combines with phospholipids to form an unusual particle that can deposit in skinfolds. Serum choles-terol can reach very high levels.

Question 32

What is ABCA-1?

Answer 32

ATP-binding transporter A1

The way that cholesterol is released to eventually be taken up by HDLs…
Cholesterol is transported actively out of cell membranes by ATP-binding Transporter A1 (ABCA-1, also sometimes called Cholesterol Efflux Regulatory Protein (CERP)).

Question 33

What is CERP?

Answer 33

Cholesterol efflux regulatory protein

ABCA-1, also sometimes called Cholesterol Efflux Regulatory Protein (CERP)

Question 34

What are clathrin-coated pits?

Answer 34

Clathrin is the protein that plays a major role in the formation of coated vesicles

Question 35

What is HTGL?

Answer 35

Hepatic triglyceride lipase

Lipoproteins of the C class (ApoCI, ApoCII) modu-late the function of lipoprotein lipase (LPL). The equivalent enzyme to LPL in the liver is hepatic tri-glyceride lipase (HTGL). LPL and HTGL are located on the surface of target cells and liberate free fatty acids and glycerol from the triglycerides in the hy-drophobic core of the lipoproteins.

Question 36

What is HSL?

Answer 36

Hormone sensitive lipase

On the adipose cell surface, hormone-sensitive lipase (HSL) releases free fatty acids into blood
Adipose tissue release these
They CAN cross membranes by breaking down triacylglycerol into free fatty acids via HSL

HSL is inhibited by insulin
Make sure we are not releasing lipids in the well fed state

Question 37

What is LCAT?

Answer 37

Lectin cholesterol acyltransferase

The way that HDLs aquire cholesterol…
Cholesterol is transferred to the HDL particles and esterified by lecitin:cholesterol acyltransferase (LCAT). This allows transport in the hydrophobic core of the HDL particles.

Question 38

What is LPL?

Answer 38

Lipoprotein lipase
Lipoprotein lipases on the sur-face of target cells cleave triacylglycerols and liberate free fatty acids from the chylomicrons

Question 39

What is nascent HDL?

Answer 39

Synthesis of the HDL particles begins in the liver and the small intestine, both of which synthesize discoidal HDL precursor particles (also called “nascent HDL”).

Question 40

What is the overflow pathway of lipid metabolism?

Answer 40

OVERFLOW pathway
After a meal, the liver has a lot more energy than it needs
It stores glycogen, but not fat unless it is a case of alcoholic fatty acid
This is the pathway the liver has come up with to get rid of the extra energy

If the liver sends out more lipids in VLDL particles than the body can consume, the blood concentration of LDLs increases. The production of LDL particles is thus often referred to as the “overflow pathway” of energy metabolism.