19 - Cholesterol and Triglycerides Flashcards
What is the role of albumin?
- 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
How do chylomicrons form?
- 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
What is the function of chylomicrons?
- 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
What is the relationship between VLDL, IDL and LDL?
Very low density lipoproteins (VLDL), intermediate density lipo-proteins (IDL) and low density lipoproteins (LDL) are maturation stages of the same particle
What is the function of VLDLs?
- 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
How do VLDLs become IDLs and LDLs?
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.
What are HDLs?
- 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
How do chylomicrons lose lipids?
Lipoprotein lipases on the surface of target cells cleave triacylglycerols and liberate free fatty acids from the chylomicrons
How do VLDLs lose lipids?
Similar to the situation in chylomicrons, VLDLs gradually lose triacylglycerols from the core of the particle through the action of lipoprotein lipases.
What are the different classes of apoproteins?
- Apoprotein A
- Apoprotein B
- Apoprotein C
- Apoprotein E
What does apoprotein A do?
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
What does apoprotein B do?
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
What do apoprotein Cs do?
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
What do apoprotein Es do?
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
What types of tests are done to assess blood lipid profiles?
Total serum cholesterol
Fasting lipid profile
Ultracentrifugation
Describe the total serum cholesterol test
Total serum cholesterol. Good approximation of serum LDL concentration. Not perfect but pretty good.
Describe the fasting lipid profile test
No dietary lipids (chylomicrons)
Consists of measurements of total cholesterol, total glycerides and HDL cholesterol
How do you determine LDL?
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!
Describe the ultracentrifugation test
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
Describe the basics of the Fredrickson classification
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.
What primary dyslipidemias exist?
Elevated cholesterol, normal triglycerides
Familial hypercholesterolemia
Familial defective ApoB100
Elevated triglycerides
Familial combined hyperlipidemia
Familial dysbetalipoproteinemia
Describe familial hypercholesterolemia
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
Describe familial defective ApoB100
Familial Defective ApoB100 (FDB) (1/10,000)
Similar to FH – defective ApoB100 prevents binding of LDL to receptor
Describe familial combined hyperlipidemia
Familial Combined Hyperlipidemia (FCHL) (1/50)
Variable etiology; may result from overproduction of ApoB100
increased production of VLDL , abundance of VLDL, IDL, LDL
Describe familial dysbetalipoproteinemia
Familial Dysbetalipoproteinemia (FDBL) (1/10,000)
Defective ApoE prevents uptake of remnants by liver
Increase in all ApoB-containing lipoproteins
What are the secondary dyslipidemia?
Obesity
Diabetes
Liver diseases
Describe the process of obesity causing a secondary dyslipidemia
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)
Describe how diabetes leads to a secondary dyslipidemia
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
What two liver diseases can cause a secondary dyslipidemia?
Liver failure (hepatitis) Cholestasis
Describe how liver failure can cause a dyslipidemia
Liver does not produce enough VLDLs and HDLs - abnormally low cholesterol and triglycerides will be seen
Describe how cholestasis can cause a secondary dyslipidemia
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.
What is ABCA-1?
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)).
What is CERP?
Cholesterol efflux regulatory protein
ABCA-1, also sometimes called Cholesterol Efflux Regulatory Protein (CERP)
What are clathrin-coated pits?
Clathrin is the protein that plays a major role in the formation of coated vesicles
What is HTGL?
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.
What is HSL?
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
What is LCAT?
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.
What is LPL?
Lipoprotein lipase
Lipoprotein lipases on the sur-face of target cells cleave triacylglycerols and liberate free fatty acids from the chylomicrons
What is nascent HDL?
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”).
What is the overflow pathway of lipid metabolism?
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.
