“I’m the kind of crazy you weren’t warned about because no one knew this level existed.”

–Usually a random girl on Instagram, but originally intended for the topic of the ANGPTL family

Remember when you were a kid and you’d ask your parents some sort of question about biology or science?  And your Dad would respond with a brief and either completely inaccurate or comically incomplete answer to your query…but since Dad was always right and you were probably already distracted by something else you just went along with it?

Well, the next topic on the docket is kind of similar.  If you’ve even heard of the angiopoietin-like protein family, specifically ANGPTL3, ANGPTL4, and ANGPTL8, you’ve probably been told that they all inhibit lipoprotein lipase.  Which is sort of true…but barely scratches the surface of their true functions.  So saddle up for a discussion on the role of the ANGPTL family in FUEL PARTITIONING. 

Guided by the axiom “Control your insulin, control your life,” we first must recognize that insulin is the primary regulator of ANGPTL3, ANGPTL4, and ANGPTL8.  And we also must recognize that, under normal physiologic circumstances, we are meant to be cycling between fasting and fed states.  When insulin is low, we ought to be in BURNING mode, partitioning fat, our savings account, toward oxidative tissues (muscles) for utilization.  Conversely, when insulin is HIGH after eating, insulin directs the ingested fatty acids toward storage in fat cells to save for later.  Given that LPL is the enzyme of interest in uptake of fatty acids in both adipocytes and myocytes, this provides the basis for the differing functions of ANGPTL3, ANGPTL4, and ANGPTL8 in different tissues at varying levels of insulin.

So before we talk about each individual ANGPTL member, here are a few concepts that will come in handy to reference, because this is a very complicated topic.  But, if I can help your head stop spinning, this will likely result in a proverbial power plant of cognitive enlightenment once the circuitry is appropriately connected.

• ANGPTL3 and ANGPTL4 inhibit LPL.
• ANGPTL3 and ANGPTL4 form complexes with ANGPTL8.  So, we can have an ANGPTL3/8 complex or an ANGPTL4/8 complex.  ANGPTL8 doesn’t do anything on its own, but it either amplifies the effect of ANGPTL3 or abrogates the effect of ANGPTL4 on LPL inhibition.
• ANGPTL3, ANGPTL4, and ANGPTL8 are all regulated by insulin levels.

ANGPTL3 is produced by the liver and inhibits LPL in oxidative tissues (muscle).  Essentially, it partitions fatty acids toward fat cells and, when it forms a complex with ANGPTL8, further inhibits LPL in muscle.  Insulin increases both ANGPTL3 and ANGPTL8, partitioning fat toward storage in adipocytes postprandially.

ANGPTL4 is produced by adipocytes and inhibits LPL in fat cells.  Consequently, ANGPTL4 is elevated during fasting, as when insulin is appropriately low, we ought to be partitioning our fatty acids toward utilization in muscle rather than storing them in fat cells.  Insulin decreases ANGPTL4 and we also know that insulin increases ANGPTL8.  When an ANGPTL4/8 complex is formed, it “inhibits the inhibition” of ANGPTL4 of LPL in fat cells, thus leading to increased LPL activity in the fat cell and a shift toward storage mode postprandially.

ANGPTL8 is expressed in both the liver and fat cells.  It is increased by insulin levels, as stated, and is incapable of inhibiting LPL on its own.

So to recap:

• When insulin is HIGH, ANGPTL3/8 inhibits LPL in muscle and partitions fatty acids toward storage in the fat cell.
• When insulin is HIGH, ANGPTL4/8 stops inhibiting LPL in the fat cell and partitions fatty acids toward storage in the fat cell.
• When insulin is LOW, ANGPTL4 does not complex to ANGPTL8, thus inhibiting LPL in the fat cell, guiding fatty acids toward utilization in muscle cells.

What we just discussed was NORMAL physiologic circumstances.  Under conditions of insulin resistance, we know that everything goes wrong, and there are numerous associations between chronically elevated levels of ANGPTL proteins and various disease states from obesity to diabetic retinopathy. (For example check out this NEW STUDY where elevated ANGPTL4 was associated with high CAC scores >400).  But what’s crazy is that these proteins involved in fuel partitioning actually are connected to our FIBRINOLYTIC SYSTEM (aka not throwing blood clots).  Check this out!

• When an ANGPTL4/8 complex is formed, this complex binds plasminogen activator (tPA) and plasminogen to generate PLASMIN, our bodies’ “clot buster.”
  • Recall, ANGPTL4/8 complexes form under normal conditions of REFEEDING.
• Plasmin then degrades both ANGPTL3/8 and ANGPTL4/8 complexes, liberating LPL and restoring GLOBAL LPL ACTIVITY.
  • However, if ANGPTL4/8 complexes DO NOT FORM under conditions of refeeding, as in insulin resistance, or if the formed complex is dysfunctional, this can lead to a PROTHROMBOTIC STATE, since functional plasmin is not generated.
    • And we know that diabesity is associated with greater tendency to form blood clots of all kinds.

I bet you didn’t have THAT on your Bingo card!  I don’t think it’s particularly earth-shattering to suggest that our bodies are meant to transition between fed and fasted states, but the link between EATING and CLOTTING is a twist that would possibly even surprise M. Night Shyamalan.  As my Aunt Lois always says (usually in reference to a dubious link between something she ate and a sore joint): “It’s ALL CONNECTED!”