cholesterol synthesis lipoproteins

What are the 4 major classes of Lipoproteins

Which apoprotein is associated with each of these? (slide 22)

1. chylomicrons

2. VLDL (very low density lipoproteins)

3. LDL (low density lipoproteins)

4. HDL (high density lipoprotein)

Where is Apo B-48 synthesized? Which lipoprotein is Apo B-48 associated with?

Small intestine, Chylomicron

What is the function of Apo C II, Apo E, and Apo B100?

Apo CII is required for LPL activation

Apo E and B-100 are required for LDL biding to LDL receptor

What is the major lipid component of chylomicrons?

TG (85-95%) and CE (1-3%)

Which lipoproteins are considered (or termed) “TG-rich lipoproteins”?

Chylomicron and VLDL

What is the function of chylomicrons?

Deliver dietary lipids (primarily TG) from intestine to adipose tissue for storage and liver for metabolism

Describe how chylomicrons transport dietary TG from small intestine to adipose tissue.

Refer to slide #28 and #31

What is the role of VLDL

Transports endogenous triglycerides (TG synthesized in the liver) to peripheral tissues (adipose tissue in the fed state and muscle in the fasted state)

Where are VLDLs synthesized?

Where do the triglycerides in VLDL come from?

Where is Apo B100 synthesized?

1. Liver in fed and fasted state

2. De novo synthesis from dietary carbohydrate

3. LCFA internalized by the liver from plasma lipoprotein remnants

4. Un-esterified or free FAs picked up by the liver from the circulation

Where is Apo B100 synthesized: in the liver

What is the metabolic fate of VLDL? (fed) versus (fasted)

fed → fat storage in adipose tissue;

In the fed state, VLDL primarily moves liver-produced triglycerides to adipose tissue for fat storage

fasted → fatty-acid oxidation in muscle.

TG-rich VLDL → loses triglycerides → smaller remnant → cholesterol-rich LDL

Where is LPL synthesized?

specifics of location

what does it do?

LPL hydrolyzes triacylglycerols in _____ and ____

adipose tissue and muscle

located on the walls of capillary endothelium within the tissue

- adipose tissue, muscle, and heart

NOT the liver

what LPL does: hydrolyzes TG to release fatty acids transported into tissue

LPL hydrolyzes triacylglycerols in _Chylomicrons_ and _VLDL_

LPL in the muscle during fasted state / exercise

• Fasting/exercise: Muscle LPL activity increases.

• ApoC-II activates LPL on muscle capillaries.

• LPL breaks down triglycerides in VLDL into fatty acids and glycerol.

• Muscle takes up the fatty acids and oxidizes them for energy.

By comparison:

• Fed state: LPL activity is higher in adipose tissue, promoting fat storage.

• Fasted/exercise state: LPL activity is higher in muscle, promoting fat oxidation.

h tissue is LPL activity for TG hydrolysis highest during fasting?

muscle

which tissue is LPL activity for TG hydrolysis highest in the fed state?

adipose tissue

Which apoprotein is required for LPL activity?

APO C-II

In which tissue does insulin stimulate LPL synthesis and secretion

Adipose tissue

Role of LDL: what are the 3 different roles of LDL?

Transport esters / cholesterol into cells:

LDL carries cholesteryl esters/cholesterol in the circulation

Delivers cholesterol to cells through LDL receptors that reorganize ApoB-100 or ApoE

Source of Cellular Cholesterol

LDL provides cholesterol to tissues that cannot synthesize enough cholesterol to meet their needs.

Regulation of Cholesterol Homeostasis

When cells take up cholesterol from LDL:

o Cholesterol synthesis decreases due to reduced HMG- CoA reductase activity.

o LDL receptor synthesis decreases.

o Cholesterol esterification and storage increases

What is the clinical significance of LDL?

Clinical Significance:

• LDL is often considered "bad cholesterol", although LDL itself is essential for normal physiology.

• Normal LDL function: Delivers cholesterol to tissues.

• Elevated LDL levels: Excess LDL can enter the arterial wall, where cholesterol accumulates and contributes to atherosclerosis (plaque formation).

LDL

Core lipids:

Apoproteins:

IDL: VLDL remnant

Core lipids:

Cholesteryl ester (35-40%) and Triacylglycerols (8-12%)

Apo B-100

LDL is produced from _____ in the bloodstream

VLDL

LDL produced form VLDL in bloodstream analogy

Think of VLDL as a delivery truck full of triglycerides leaving the liver:

o The VLDL “truck” delivers triglycerides to adipose tissue and other peripheral tissues.

o As triacylglycerols are removed, the particle becomes smaller and denser, forming IDL.

o After most of the triglycerides have been unloaded, the remaining particle is converted into LDL, a cholesterol-rich lipoprotein.

Explain LDL as a receptor

LDL receptor is a single-pass transmembrane glycoprotein

o It contains the Apo B-100 and Apo E binding site

o Cells take up LDL by LDL receptor-mediated endocytosis

o After LDL binds to its receptor, the receptor-LDL complex is internalized via endocytosis and delivered to an endosome

o Cholesterol carried by LDL is utilized by cells for the synthesis of cellular membranes and, in steroidogenic tissues, for the synthesis of steroid hormones.

what is the role of LDL as a receptor

The number of LDL receptors on the cell surface plays a critical role in controlling blood LDL cholesterol levels.

o LDL receptors bind LDL particles and remove them from the circulation by mediating their uptake into cells.

o The number of LDL receptors determines the rate of LDL clearance from the bloodstream o

More LDL receptors = lower blood LDL levels

o When cells express more LDL receptors, they take up more LDL particles from the bloodstream, reducing the concentration of LDL cholesterol in the blood.

Fewer LDL receptors = higher blood LDL levels

o When receptor numbers decrease, less LDL is removed from circulation, causing LDL cholesterol to accumulate in the blood.

What happens when cholesterol enters a cell? (liver cell, enterocyte, macrophage)

Cholesterol + Fatty Acyl CoA ——ACAT—→ Cholesteryl Ester

ACAT: acyl CoA

What is the role of cholesterol ester

1. Serves as a storage of cholesterol in cells

2. Provides cholesterol for the synthesis of bile acids and steroid hormones

3. Supplies cholesterol as a core lipid for the formation of chylomicrons and VLDL

4. Contributes to the formation of cholesteryl ester-rich foam cells during atherosclerosis

5. Can be hydrolyzed by HSL or cholesteryl ester hydrolase to release free cholesterol when needed

1. What is the major lipid component of LDL and IDL?

2. Which apoprotein is associated with each of these?

3. How are IDL and LDL converted from VLDL?

4. What is the function of LDL?

1. cholesterol ester

2. Apo E associate with LDL; Apo E and Apo B-100 associated with IDL

3. VLDL —→ IDL ——> LDL

4. Deposits Cholesterol into peripheral cells (non-liver cells)