Reverse Cholesterol Transport

Sections

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LIPOPROTEIN METABOLISM

• Exogenous pathway: chylomicrons clear dietary lipids
• Endogenous pathway: VLDL and LDL transport/distribute endogenously synthesized lipids
• Reverse cholesterol transport: HDL clears excess plasma cholesterol

Enzymes

• Degrade triacylglycerol to glycerol and free fatty acids

1. Lipoprotein lipase (LPL), bound to the endothelial layer of peripheral capillaries.
2. Hepatic lipase, localizes within hepatic endothelial cells.

HIGH DENSITY LIPOPROTEIN (HDL)

• "Good cholesterol"
• Transports second most cholesterol (first LDL)
• Reservoir for lipoproteins

REVERSE CHOLESTEROL TRANSPORT
Step 1: Liver and small intestine synthesize nascent HDL

• Disc shape with ApoA-I and ApoA-II
• Heterogeneity exists: nascent HDL may have ApoA-I only, ApoA-II only or both
  Step 2: Nascent HDL picks up free cholesterol from peripheral tissues to become HDL3
  Step 3: Nascent HDL picks up LCAT from plasma as it becomes HDL3

Lecithin acyl transferase (LCAT) esterifies free cholesterol

HDL3

• Circular HDL particle with CE (esterifies free cholesterol with LCAT)
• Apolipoproteins on surface: ApoA-I, ApoA-II, ApoE & ApoC-II
• Circulating lipoproteins donate ApoE and ApoC-II to HDL3
  Step 4: HDL3 picks up more free cholesterol to become HDL2

HDL2

• Larger HDL particle with more CE (same lipoproteins as HDL3)
• Contains cholesterol ester transfer protein

Cholesterol ester transfer protein (CETP) transfers lipids between HDL and VLDL

• Activated by ApoA-II
  Step 5: CETP transfers CE (from HDL) to VLDL, and TAG (from VLDL) to HDL
• Endogenous pathway: VLDL eventually degrades to LDL (redistributes cholesterol)
  Step 6: HDL2 binds scavenger receptor (SR-B1) on liver
• HDL2 continues accumulating plasma cholesterol before binding
• Hepatic lipases degrade TAG & membrane phospholipids: HDL2 --> HDL3
• Liver converts excess cholesterol to bile salts (digestive elimination)

CLINICAL CORRELATION

Corneal clouding

• Symptom of LCAT or ApoA-I deficiency
• HDL cannot esterify cholesterol
• Leads to rapid HDL degradation: excess cholesterol deposits in cornea and peripheral vessels

Full-Length Text

• Here we will learn reverse cholesterol transport.

• To begin, start a table to learn the three key pathways in lipoprotein metabolism.
  • Exogenous pathway, in which chylomicrons clear dietary lipids.
  • Endogenous pathway, in which VLDL and LDL transports and distributes endogenously synthesized lipids (those synthesized in the body).
  • Reverse cholesterol transport, in which HDL clears excess cholesterol.

In this tutorial, we will learn the last pathway: reverse cholesterol transport.

• Now, denote that there are two key enzymes involved in lipoprotein metabolism:

• Denote that both enzymes degrade triacylglycerol to glycerol and free fatty acids.
  • Lipoprotein lipase, which is bound to the endothelial layer of peripheral capillaries.
  • Hepatic lipase, which is localized in hepatic endothelial cells.

• Denote that hepatic lipase is also a phospholipase: it can degrade phospholipids.

We will focus primarily on hepatic lipase, here.

Now, let's illustrate reverse cholesterol transport.

• To begin, draw a liver, which converts cholesterol to bile acids for excretion.

• Draw peripheral tissues.
  • Peripheral tissues release free cholesterol due to membrane turnover or cell death.

Finally, let's illustrate how HDL picks up this excess cholesterol and returns it to the liver for excretion.

First, let's review some key points about HDL.

• Write that HDL is often referred to as "good cholesterol" because it clears excess cholesterol from the blood.

• Indicate that while LDL is the major cholesterol carrier in the body, HDL transports the second most.

• Finally, write that HDL is a reservoir of apolipoproteins, a concept we will return to.

Now, let's illustrate how HDL is synthesized.

• Step 1: the liver and small intestine synthesize nascent HDL.

• Draw a disc-shape with two apolipoproteins on its surface: A-I and A-II. This is our nascent HDL.

Before we continue with our specific steps, we need to introduce HDL 3.

• Draw HDL 3 as a circular HDL particle that contains cholesterol esters; it also contains other lipids, but we leave them out of our diagram for simplicity.

• Include A-I and A-II on its surface, just like nascent HDL.

• Show that circulating lipoproteins donate ApoE and ApoC-II to the surface of HDL 3.
  • We use reversible arrows to emphasize that HDL functions as a reservoir for apolipoproteins: it donates them to chylomicrons and VLDL in the exogenous and endogenous metabolic pathways.

• Step 2: show that nascent HDL picks up free cholesterol from the peripheral tissues to become HDL3.

• Then, to show how HDL3 esterifies the free cholesterol, we need to introduce the enzyme: LCAT (lecithin cholesterol acyl transferase).

• Step 3: Show that in the process of forming HDL 3, the nascent HDL picks up the enzyme LCAT from the plasma.

• And write that LCAT esterifies the free cholesterol in HDL.
  • We can think of LCAT as being similar to the liver enzyme: ACAT.

• Indicate that Apo-A1 activates LCAT.

• As a clinical correlation, write that corneal clouding is a symptom of LCAT or ApoA-I deficiency.
  • HDL cannot esterify cholesterol, which leads to its rapid degradation.
  • Without HDL, excess cholesterol deposits in regions such as the cornea and peripheral vessels.

• Next, to set up step 4, redraw HDL 3 as HDL2, which is a larger HDL particle because it contains even more cholesterol than HDL3.

• Include the apolipoproteins on its surface.

• Step 4: Show that as HDL3 circulates, it picks up even more free cholesterol from the peripheral tissues to become HDL2.

• Next, to set up step 5, draw VLDL.

• Indicate it mainly carries triacylglycerol.

• Then, indicate that HDL2 contains an enzyme CETP (cholesterol ester transfer protein), which facilitates the transfer of lipids between HDL and VLDL.

• Step 5: Illustrate that CETP facilitates the transfer of CE to VLDL in exchange for triacylglycerol.

• Indicate that via the endogenous pathway, VLDL eventually degrades to LDL, which redistributes cholesterol to the liver and peripheral tissues.

• Indicate that the surface protein AII activates CETP.

• Step 6: Draw a scavenger receptor (SR-B1 in particular) on the liver.

• Show that HDL2 (which continues to accumulate cholesterol from the plasma) binds it and transfers cholesterol esters to the liver.

• And that Hepatic lipases degrade TAG and membrane phospholipids, so HDL 2 converts back to HDL 3.

• Lastly, indicate that the liver can then convert this excess cholesterol into bile salts, which it eliminates via the digestive tract.