Lipid Metabolism › Lipoproteins

Endogenous Pathway

Notes

Endogenous Pathway

Sections

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.

VERY LOW DENSITY LIPOPROTEIN (VLDL)

  • 90% lipids
  • T1/2 ~ hours
  • ApoB-100: liver-derived lipoprotein marker

LOW DENSITY LIPOPROTEIN (LDL)

  • ApoB-100
  • T1/2 ~ days
  • Major cholesterol carrier

ENDOGENOUS PATHWAY

  • Liver : primary site of de novo lipid synthesis
  • Lipoproteins in endogenous pathway all have ApoB-100
    Step 1: Endogenously synthesized lipids packaged into VLDL in liver (ApoB-100)
    Step 2: HDL donates ApoC-II & ApoE to VLDL
  • VLDL trades TAG for HDL's CE
    Step 3: ApoC-II binds/activates LPL (peripheral tissues)
    Step 4: LPL degrades TAG into glycerol & FFA
  • FA enter tissues & glycerol returns to liver
    Step 5: VLDL become IDL (1. TAG 2. Free/esterified cholesterol)
  • IDL: ApoE & ApoB-100.
    Step 6: IDL Apo E binds receptor on liver
    Step 7: Hepatic lipase degrades TAG
  • IDL becomes LDL (1. CE 2. TAG & free cholesterol)
  • LDL = major cholesterol carrier in body
    Step 8: two options
    i. LDL returns to liver
    ii. LDL deliver contents to peripheral tissues
  • Binds LDL receptors = endocytosis & cholesterol release

CLINICAL CORRELATION

Familial hypercholesterolemia

  • Hereditary disease
  • LDL receptor or ApoE deficiency
  • Elevated plasma LDL (hyper-cholesterol)
  • TAG normal
  • Xanthomas: yellow cholesterol-rich deposits, can occur anywhere in the body

Full-Length Text

  • Here we will learn the endogenous pathway of lipoprotein metabolism.
  • 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 focus on the endogenous pathway, but we will note similarities with the exogenous pathway as we proceed.

  • 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 which localizes within hepatic endothelial cells.

Now, let's illustrate the endogenous pathway.

  • Draw a liver, the primary site of de novo lipid synthesis.
  • Draw a capillary adjacent to a representative section of peripheral tissues.

Now, let's review some key points about VLDL particles, which initiate the endogenous pathway:

  • Draw a VLDL particle in the liver.
  • Indicate that lipids comprise about 90% of its contents.
  • Show that it carries primarily endogenously synthesized triacylglycerol (TAG).
  • And secondarily cholesterol esters (CE) and free cholesterol (C).
    • Make a note of these abbreviations for reference.
  • Draw apolipoprotein B-100 on its surface (we will use this semicircle to represent apolipoproteins from now on) and write that it is a marker of liver-derived lipoproteins.
    • This is different from ApoB-48 on the surface of chylomicrons.
    • ApoB-48 is a marker of dietary lipids, deriving from the small intestine.
  • Finally write that a VLDL particle's half-life is on the order of hours long; this is greater than chylomicrons, which clear in minutes.

Now, let's illustrate the endogenous pathway.

  • Step 1: Endogenously synthesized lipids are packaged into a VLDL in the liver.
  • Step 2: We'll show that much like with chylomicrons, HDL donates its apolipoproteins to the VLDL.
  • Redraw the VLDL with B-100 on its surface.
  • Then, draw 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).
  • Next, show that HDL donates its apolipoproteins to the VLDL.

Next, indicate that HDL and VLDL exchange lipids as follows:

  • The VLDL trades TAG for the HDL's cholesterol esters.
    • This does not occur in the exogenous pathway.

Next, draw the endothelial layer of our capillary.

  • Draw lipoprotein lipase (LPL) in the capillary lumen and show it anchored to the endothelium.

Step 3 and 4 are identical to chylomicron metabolism.

  • Step 3: show that ApoC-II binds LPL and activates it.
  • Step 4: LPL degrades TAG into glycerol and free fatty acids.
  • Indicate that glycerol returns to the liver.
    • Glycerol can be metabolized to DHAP, which is a substrate of gluconeogenesis.
  • Indicate that free fatty acids enter the peripheral tissues.
  • For step 5, draw an intermediate density lipoprotein (IDL), which is what VLDL becomes when LPL degrades their TAG.
  • Show that the IDL still carries primarily TAG
    • And, secondarily, cholesterol ester and free cholesterol.
  • And draw ApoE and ApoB-100 its surface.

What happens to ApoC-II?

  • Redraw HDL (which is primarily cholesterol esters, secondarily TAG and free cholesterol).
  • On its surface, again include ApoE and ApoC-II.
  • Indicate that just like with chylomicron metabolism, here, ApoC-II returns to HDL, which prevents further lipoprotein lipase activation.

Intertextual variation exists regarding the following steps. Many sources refer to another intermediate called a VLDL remnant; others suggest that IDL particles can also derive from chylomicron remnants. The pathway we introduce consolidates the consistencies between the many suggested pathways.

  • Step 6: Draw a receptor on the liver.
  • Write that IDL Apo E binds it (as we saw with chylomicron remnants).
  • For Step 7: Draw an LDL. We'll add its surface proteins shortly.
  • Indicate that it contains primarily cholesterol esters and secondarily TAG and free cholesterol.
    • It is the major cholesterol carrier in the body.
  • Now, show that hepatic lipases degrade IDL triacylglycerol and membrane phospholipids to produce this LDL.
  • Indicate that HDL picks up ApoE from the IDL.
  • Now, draw ApoB-100 on the LDL surface.
    • All the lipoproteins in this pathway have ApoB-100.
  • Step 8: indicate that from here, LDL may travel back to the liver or deliver its contents to the peripheral tissues.
  • Write that either way, LDL binds LDL receptors, initiating endocytosis.
    • Cholesterol is released in the cell.
  • Write that:
    • In the liver, cholesterol can be excreted as bile acids.
    • In the peripheral tissues, it can be used to synthesize steroid hormones or vitamin D.
  • Finally, write that the half-life of an LDL particle is measured on the order of days, much longer than that of both chylomicrons and VLDL particles.
  • As a clinical correlation, denote that Familial hypercholesterolemia is a hereditary disease that results from a deficiency in either LDL receptors or ApoE.
    • Patients suffer elevated LDL levels (hence hyper-cholesterol), while TAG levels remain normal.
    • A common symptom is the appearance of xanthomas, which are yellow cholesterol-rich deposits that can occur anywhere in the body as the disease progresses.
    • In fact, scientists believe that the Mona Lisa exhibits an early case of familial hypercholesterolemia because a small yellow xanthoma can be found at the corner of the subject's left eye!