Given that there are now two ApoC3 inhibitors approved by the FDA (Olezarsen and Plozasiran),  ApoC3 has recently moved from the Deep End of the Community Pool to slightly more mainstream waters.  We previously discussed the topic HERE, but briefly, ApoC3 is the “Great Inhibitor” of hepatic ApoB-lipoprotein uptake as well as an inhibitor of lipoprotein lipase (LPL).  And in kinetic studies of people with ApoC3 loss-of-function whose “inhibitors are inhibited,” there is increased turnover of VLDL and IDL particles.  Essentially, the ApoB-100 Mailmen (VLDL and IDL particles in this case) deliver the triglyceride mail and then go right home to the liver at the end of their shifts.  This results in enhanced clearance of ApoB-100 particles and, in heterozygotes (spoiler alert), we don’t observe increased ApoB production that would offset the enhanced clearance.  Ergo, it makes sense that folks with loss-of-function ApoC3 have lower triglycerides and decreased risk of cardiovascular events in various studies.  One of these specific variants found in the Lancaster Amish is called the R19x, which results in an “Amish Paradise” where these individuals have far less incidence of CAC compared to non-carriers.

But as mentioned, the most encouraging observations in folks with ApoC3 loss-of-function, to this point, have been in HETEROZYGOTES.  They still have some ApoC3 activity, but less than the normal population.  So if heterozygotes seem pretty well-off, homozygotes (with hardly any ApoC3) should be PRACTICALLY INVINCIBLE, right?

Well, a Pakistani study of folks homozygous for ApoC3 loss-of-function gives us some preliminary insight.  The population studied was notable for CONSANGUINITY, which is a fancy euphemism for INBREEDING.  Ideal for studying lipids, but maybe not ideal for being not gross.

So interestingly, the ApoC3 loss-of-function homozygotes displayed the following compared to their heterozygote counterparts:

–Higher Lp(a): (45.5 mg/dL vs 21.6 mg/dL)

–Higher ApoB: (92 mg/dL vs 75 mg/dL)

They still had low triglycerides, BUT the homozygotes had increased VLDL production rates and significantly increased production of both IDL and LDL.  In fact, IDL production rose a whopping 319%, and the conversion rate of VLDL to IDL increased 185%!  If you’re a Lipid Specialist, you’re probably starting to speculate about the potential consequences of increased IDL remnants (Type III dysbetalipoproteinemia).  And with the limited observational data we possess, there does not appear to be a decrease in coronary disease among people homozygous for ApoC3 loss-of-function.

So what can we learn from this?  If you are heterozygous for ApoC3 loss-of-function, maybe don’t marry your cousin.  And maybe a little ApoC3 is better than none…but as always, there is much more to learn!