BIOC 503 - Lipoproteins

lipoproteins

Proteins associating with lipids to carry out the function of transporting complex lipids into the bloodstream.

intestine

Chylomicrons transport complex lipids from the ___ to other tissues and are degraded by protein lipases before being reabsorbed by the liver.

spherical

Lipids are carried through the plasma on ___ particles made of proteins, phospholipids, cholesterol, TAGs, and cholesteryl esters.

surface

Cholesterol, phospholipids, and proteins are found on the ___ of lipoproteins carrying lipids through the plasma because they have a head group, are a minimum polar, hydrophilic, or amphipathic.

inside

Triacylglycerols (TAGs) and cholesteryl esters are on the ___ of lipoproteins carrying lipids through the blood because they are completely saturated/hydrophobic.

density

Lipoprotein particles were named based on the position of sedimentation in the centrifuge, aka based on their density.

chylomicrons

Largest, least dense lipoproteins

• least dense = less protein content

• large = lots of TAGs

very low-density lipoproteins

aka VLDL

smaller but denser than chylomicrons

• not a lot of protein content still, but more than chylomicrons because denser

• still a lot of TAGs content, but less than chylomicrons because smaller

decreases

The TAGs content of lipoproteins ___ with smaller size and higher density

increases

protein and phospholipids content ___ with smaller size and higher density

• make sense because density is due to protein content

low density lipoproteins

aka LDL

smaller but denser than VLDL and chylomicrons

• lower TAGs content because smaller than chylomicron and VLDL

• higher cholesteryl esters content because function is to deliver lipids/fatty acids to non-hepatic tissues

• higher protein content than VLDL and chylomicrons because denser

high density lipoproteins

aka HDL

smallest and densest lipoprotein

• function is to carry out reverse cholesterol pathway

• highest protein content

• lowest TAGs content (as it has to pick them up)

• low cholesteryl esters content (as it has to pick them up)

apoliproteins

proteins that are part of a lipoprotein particle

• provide sites for the particle to bind to cell surface receptors, activate enzymes, etc.

Exogenous pathway

Chylomicrons carry dietary fat to tissues and remnant chylomicrons bring the extra to the liver.

1. Dietary fats get broken down and the TAGs are packed up in chylomicrons (least dense lipoprotein)

2. Chylomicrons go to the blood stream 

3. ApoC-II activates lipoprotein lipases to break down TAGs and release free fatty acids to tissues, also release cholesterol

4. Depleted chylomicrons remnants go back to the liver 

5. ligand ApoE on their cell membrane allows detection by liver receptor triggering endocytosis and recycling

6. Release extra TAGs and cholesteryl esters into liver for breakdown

Endogenous pathway

VLDL transports body lipids to adipose tissue and muscles, them VLDL remnants become LDL, which is transported back to liver.

1. Liver converts excess body fat/carbohydrates (read not used as fuel) into TAGs and cholesteryl esters

2. TAGs and cholesteryl esters packages into VLDL inside the liver

3.  VLDL released into the bloodstream

4. ApoC-II activates lipoprotein lipases to release free fatty acids to tissues 

5. adipose tissues re-esterify them to store them as lipid droplets, muscle tissues use them for energy

6. Depleted VLDL becomes LDL which is richer in cholesterol and cholesteryl esters

7. ApoB-100 is the LDL ligand binding to cells LDL receptor allowing receptor-mediated endocytosis

8. LDL endosome merge with lysosome

9. lytic enzyme release cholesterol, fatty acids, and amino acids

10. cholesterol goes to the ER, inhibiting synthesis

11. LDL not picked up by cells go back to liver

familial hypercholesterolemia

aka FH

disease due to mutation(s) on the LDL RECEPTOR, preventing normal LDL uptake by the liver and other tissues, thus making it accumulates in the bloodstream

• leads to atherosclerosis

• cholesterol accumulates in blood

• increased risk of heart attack

Niemann-Pick type C

aka NPC

disease due to a mutation causing cholesterol to be restrained to the lysosome, not going to the ER and thus not inhibiting cholesterol synthesis.

• defect in lipid storage

• mutation NOT ON THE RECPTOR & need mutation on BOTH alleles this time (homozygous genotype required)

• accumulation of cholesterol in liver, brain, and other tissues

• leads to premature death

Reverse transport pathway

HDL carries cholesterol from chylomicron and VLDL remnants (aka LDL) back to the liver

1. HDL pushed into bloodstream as a small, very dense lipoprotein aka with high protein content

2. HDL picks up VLDL remnants, LDL, and chylomicrons cholesterol (ApoA-1 receive cholesterol from inside of foam cells from carrier ABCA1, and HDL receive cholesterol from foam cell membrane)

3. LCAT enzyme (lecithin-cholesterol acyl transferase) convert then to cholesteryl esters 

4. HDL is now bigger and less dense, aka mature HDL, it returns to the liver to drop off its fat content

lecithin-cholesterol acyl transferase

the ___ enzyme (LCAT) is partially made of lecithin (aka phosphatidylcholine = PC) whose group in 2nd position is used to esterify cholesterol

• creates cholesteryl ester

• creates lysolecithin aka lecithin but the second position is linked to hydroxy (-OH) group just like in glycerol

ATP-Binding Cassette

___ (ABC) transporters are found in foam cells and transport cholesterol from inside or the surface of foam cell to HDL

ABCA1

Transport cholesterol from the INSIDE of the foam cell, associate/deliver it to protein ApoA-1 on HDL

ABCG1

transport cholesterol from the surface of foam cell to HDL

foam cell

cell formed when mature macrophage absorbs too much oxidized lipids from lumen of blood vessels 

• LDL with partly oxidized lipids attract immune cells

• macrophages do not regulate cholesteryl esters and sterol intake

• become ____

• attach to blood vessels and form plaque

• causes more immune cells to be recruited

• can clog artery

ratio

the medicinal biomarker for cholesterol is the ___ of total cholesterol and HDL

acetate (acety-CoA)

all carbon from cholesterol are derived from this one metabolite of carbohydrates

NADPH, cleavage of high energy phosphate and thioester bonds

Catabolic pathways either directly produce ATP or produce reducing equivalents that are used to generate ATP via the electron transport chain. In contrast, synthetic pathways such as cholesterol biosynthesis consume energy and use reducing equivalents of which form?

catalyzes reduction of HMG-CoA

HMG-CoA reductase is the name of the enzyme that ___

insulin de-phosphorylate (aka deactivates) HMG-CoA reductase

Short term regulation of cholesterol biosynthesis by hormones occurs by covalent modification of HMG-CoA reductase, how?

HDL, LDL, VLDL, Chylomicron

Unlike proteins and carbohydrates, transport of lipids including cholesterol requires lipoproteins. The triglyceride content determines their density. If arranged from lowest to highest triglyceride content, which order is correct?

defective hydrolysis of triglycerides in capillary walls due to lack of lipoprotein lipase activation

In addition to the major structural proteins, all lipoproteins also contain additional proteins that impart specific functions. What will be the consequence of ApoCII deficiency and why?  

A

Which of these statements about the regulation of cholesterol synthesis is not true?

A) Cholesterol acquired in the diet has essentially no effect on the synthesis of cholesterol in the

liver.

B) Failure to regulate cholesterol synthesis predisposes humans to atherosclerosis.

C) Cholesteryl ester is synthesized from remnant chylomicrons by LCAT present in HDL

D) Insulin stimulates HMG-CoA reductase.

D

HDL is considered the “good cholesterol” because it brings cholesterol back to the liver from the peripheral tissues including plaque associated foam cells. But mere increase in plasma HDL cholesterol (HDL-C) levels is not a true predictor of protection from cardiovascular disease risk: Why?

A. It is the final removal of cholesterol from the liver that is more important than increase in plasma HDL-C alone

B. Increase in plasma HDL-C can also mean reduced delivery through SR-BI

C. Increase in plasma HDL-C does not necessarily mean that cholesterol is removed from macrophages at a higher rate

D. All of the above

C

Which of the following has highest cholesterol content?

A.Chylomicron

B.VLDL

C.LDL

D.HDL

D

Which of the following is the common substrate of both fatty acid and cholesterol biosynthesis

A.Fatty acyl-CoA

B.Malonyl- CoA

C.Propionyl-CoA

D.Acetyl-CoA