Chylomicron Metabolism

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.

CHYLOMICRONS

• Fed state only
• Cleared ~ minutes
• 98% lipids (1.TAG 2. Free/esterified cholesterol)
• ApoB-48 = dietary lipoprotein marker

EXOGENOUS PATHWAY

• Only occurs in the fed state.
• Clears dietary lipids
  Step 1: Dietary lipids are packaged into a chylomicron
  Step 2: Chylomicron enters lymphatic system (empties into circulation via left subclavian vein)
  Step 3: HDL donates ApoE and ApoC-II to chylomicron
  Step 4: ApoC-II binds/activates LPL (peripheral tissues)
  Step 5: LPL degrades TAG into glycerol & FFA
• FA enter tissues & glycerol returns to liver
• Chylomicron = chylomicron remnant (low TAG, high CE and C)
  Step 6: ApoC-II returns to HDL
  Step 7: Apo E binds liver remnant receptor: chylomicron endocytosis
  Step 8: Remnant releases cholesterol in liver
• Remnant degraded by lysosomes

CLINICAL CORRELATION

Familial Hyperchylomicronemia

• Rare hereditary disease
• LPL or ApoC-II deficiency: cannot clear chylomicrons
• Fasting blood plasma: cloudy
• Lipemia retinalis: cloudy appearance of capillaries in the retina

Full-Length Text

• Here we will learn how the body metabolizes chylomicrons.

• 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 transport and distribute endogenously synthesized lipids (those synthesized in the body).
  • Reverse cholesterol transport, in which HDL clears excess cholesterol.

In this tutorial, we will learn the exogenous pathway.

• Now, let's denote the two key enzymes involved in lipoprotein metabolism, which both degrade triacylglycerol to glycerol and free fatty acids.
  • Lipoprotein lipase, which is bound to the endothelial layer of peripheral capillaries.
  • Hepatic lipase, which is also a phospholipase (meaning it can degrade phospholipids) and localizes within hepatic endothelial cells.

We will only see lipoprotein lipase in this pathway.

Now, let's illustrate the exogenous pathway.

• First, draw a small intestine epithelial cell, which will house the chylomicron.

• Then, draw representative peripheral tissues

• And a capillary adjacent to them.

• Then, draw the liver.

Now, let's draw the exogenous pathway.

• Make a notation that it only occurs in the fed state.

• Why?
  • Because its purpose is to clear dietary lipids.

Let's illustrate this, now.

To understand the exogenous pathway, we first need to understand what chylomicrons are, which clear dietary lipids.

• Draw a chylomicron within the intestinal cell; it is the largest and least dense of the lipoproteins.

• Write that chylomicrons:
  • Are only synthesized in the fed state.
  • Are cleared from the body within minutes.
  • Are 98% lipids, primarily they are dietary triacylglycerols (TAG)'s.
  • Secondarily, they are cholesterol esters (CE) and free cholesterol (C).

Let's note these abbreviations for reference.

• Next, draw a semicircular shape on the chylomicron surface to represent an apolipoprotein.
  • We will use this shape to represent apolipoproteins throughout this tutorial.

• Label it B-48 and indicate that ApoB-48 is a marker of dietary lipoproteins.

Now we're ready for the steps in the exogenous pathway.

• Step 1: Dietary lipids are packaged into a chylomicron, which is synthesized in the endoplasmic reticulum.

• Step 2: Show that the chylomicron enters the lymphatic system, which empties into the circulation via the left subclavian vein. Thus, chylomicrons enter circulation, here.

• Step 3: Draw an HDL.

• Show that it primarily comprises cholesterol esters.

• Secondarily, comprises TAG and free cholesterol.

• On its surface, draw ApoE (E in a crescent shape)

• And ApoC-II (CII in a crescent shape).

• Then, show that HDL donates these surface apolipoproteins to the chylomicron.
  • HDL functions as an apolipoprotein reservoir.

• Then, draw the endothelial layer of the capillary.

• Show that lipoprotein lipase (LPL), which is an enzyme in the capillary lumen, is anchored to this layer.

• Step 4: ApoC-II binds LPL and activates it.

• Step 5: LPL degrades chylomicron TAG into glycerol and free fatty acids.

• Show that glycerol returns to the liver, where it can be metabolized to DHAP, a substrate of gluconeogenesis.

• Show that the chylomicron's free fatty acids enter the peripheral tissues: particularly the mammary glands, adipose and muscle tissues.
  • Free fatty acids are stored in adipocytes or oxidized for energy in muscle cells to fuel contractions.

• This step also occurs in the endogenous pathway; lipoprotein lipase allows circulating lipoproteins to degrade and distribute their cargo.

• Show that the chylomicron is now a chylomicron remnant.
  • It is primarily cholesterol esters.
  • Secondarily, triaclyglycerol and free cholesterol.

• Indicate that it still contains Apo B-48 and Apo E on its surface.

• But, for step 6, show that Apo CII returns to HDL, which prevents further LPL activation.

• Draw a remnant receptor on the liver.

• Step 7: Apo E binds it and the chylomicron is endocytosed.

• Step 8: the remnant releases its cholesterol in the liver, and is finally degraded by lysosomes.

• Recall, chylomicrons are cleared within minutes, thus this entire process (from chylomicron synthesis to remnant degradation) occurs very rapidly.

• As a clinical correlation, write that Familial Hyperchylomicronemia is a rare hereditary disease in which patients cannot clear chylomicrons efficiently.
  • It can be a result of either LPL deficiency or ApoC-II deficiency. As we have seen, ApoC-II activates LPL.

Imagine that we study a healthy patient's blood plasma sample after fast.

• The blood plasma is relatively translucent.
  • It is cleared of chylomicrons.

• When we collect blood plasma after a meal, however, the chylomicrons produces give it an opaque, milky appearance.

• In patients with familial hyperchylomicronemia, a blood plasma sample looks cloudy even after fast.
  • Lipemia retinalis, the cloudy appearance of capillaries in the retina, is a common symptom of this disease.