Unexpected cameos and unlikely showdowns often end up being among the most memorable moments in movies. I don’t think anyone was expecting Bob Barker from The Price Is Right to lay a beatdown on Adam Sandler in Happy Gilmore, but I don’t think any of us will ever forget that scene!

And similarly, I don’t think anyone was expecting the Portly Postprandial Postmen (triglyceride-laden chylomicrons) to lay a beatdown on the Lp(a) “Felons of the Lipid Neighborhood,” but THIS ARTICLE suggests that those with Familial Chylomicronemia Syndrome end up with MUCH LOWER Lp(a) levels than would be expected based on the genetic factors that typically dictate Lp(a) production!

So this topic is very technical and requires regular residency in Lipid Land, and you can read more about Lp(a) in Chapter 6 of THIS BOOK and Familial Chylomicronemia Syndrome in the “Remixed 2^nd Edition” of that book.  But I’ll give you a few brief key points so we can hopefully appreciate the findings in this publication:

• Severe hypertriglyceridemia (sHTG) due to Familial Chylomicronemia Syndrome (FCS) is due to a near-complete deficiency in Lipoprotein Lipase (LPL) or a biallelic loss-of-function variant in alleles (such as GPIHBP1, APOA5, LMF1, and APOC2) essential for LPL function.  LPL is produced by adipocytes and myocytes and is critical for either storing triglycerides in the fat cell or taking them up into the muscle cell for subsequent utilization.  Folks in the BALANCE study referenced in the article had true FCS, which is characterized by a predominance of ApoB-48 chylomicrons (Postprandial Postmen) who are incapable of delivering their triglyceride packages.  There is a relative paucity of ApoB-100 VLDL and remnant particles in this particular disease state, but a profoundly increased risk of pancreatitis.
• Conversely, sHTG (commonly defined as levels >500 mg/dL) due to Multifactorial Chylomicronemia Syndrome (MCS) is often due to various factors, such as insulin resistance, alcohol use, and medications, that magnify a genetic predisposition to a Lazy and Loitering Postal Service.  Although chylomicrons are part of this picture, there are much more VLDL and remnant particles in this disease state, as some degree of LPL activity is retained.

Most of the people who get their medical information from Instagram reels have already unsubscribed by this point, but stick with me for just a few preliminary points about Lp(a):

• Lp(a) is comprised of various Kringle Domains, and these Dastardly Danish Protein Pastries serve important roles in the synthesis and function of Lp(a). Production of Lp(a) is genetically determined and dictated by the production rate; this production rate is determined by the number of repeats on Kringle IV subsegment 2 (KIV-2).  The fewer repeats on KIV-2, the more particles that are produced per unit time. (In today’s study, <17 repeats is the cutoff for the smallest isoforms).  In general, fewer KIV-2 repeats = More production of Lp(a) Felons in your Lipid Neighborhood.
  • Just in case this is confusing, let’s shift metaphors to jewelry, since it’s probably someone’s wedding anniversary out there!  Let’s say you genetically make 100 mg/dL of Lp(a) Pearl Necklaces.  You could make a necklace every 25 pearls (analogous to 25 KIV-2 repeats), so you would have 4 Lp(a) Necklaces total (4 particles).  Or, you could make a necklace every 10 pearls, so you would have 10 Lp(a) Necklaces.  In this case, you don’t want more necklaces…you’ll look like one of those pro athletes who looks ridiculous because he’s wearing 19 chains while playing football.  No wonder they have massive necks and huge traps!
• Kringle IV-10 carries OXIDIZED PHOSPHOLIPIDS, which are thought to contribute to the Atherosclerotic Infractions committed by Lp(a) in the arterial wall.  This can be quantified by OxPL-apoB (and OxPL-apo(a) measurements), and oftentimes much of the OxPL-apoB found in human plasma is present on Lp(a) particles.

Now FINALLY we can get into the summary points of this article!

• Those with FCS from the BALANCE trial were compared to the placebo arm in the ESSENCE-TIMI-73b trial (which I wrote about HERE).  The folks with FCS had fasting triglycerides north of 2,000 mg/dL, whereas the ESSENCE people were only around 268 mg/dL.
• Lp(a) levels in those with FCS were, on average, MUCH LOWER than those from ESSENCE-TIMI-73b who had modestly elevated triglycerides, but who didn’t have LPL deficiency.
  • Even in those with smaller isoforms of KIV-2, which would typically lead to higher production rates of Lp(a) particles, those with FCS had 61-83% lower Lp(a) levels than those without!
    • KIV-2 repeats <17 Without FCS: 175 nmol/L
    • KIV-2 repeats <17 WITH FCS: 67.4 nmol/L
    • KIV-2 repeats 17-20 Without FCS: 138 nmol/L
    • KIV-2 repeats 17-20 WITH FCS: 23.9 nmol/L
  • Predictably, median OxPL-apoB levels were 45% lower in those with FCS than their counterparts without FCS.
    • OxPL-apo(a) levels were also about 10x lower in those with FCS!
• Given this inverse relationship between triglyceride levels and Lp(a) levels, you might think that treatment with an APOC3 inhibitor like Olezarsen would affect Lp(a) levels, since it markedly reduces triglyceride levels in those with FCS…
  • But that doesn’t seem to be the case!

So this is fascinating, and we don’t have the clear answer as to why we observe this phenomenon.  But the authors speculate that the lack of LPL-dependent lipolysis in FCS interferes with Lp(a) synthesis in ways that are independent of the triglyceride levels themselves. In non-FCS situations, even when triglycerides are quite elevated, some degree of LPL activity and lipoprotein remodeling into smaller apoB-100 species is retained.

And this may be a case of “Size DOES Matter.”  Remember, for Lp(a) to commit Cholesterol Crimes, it needs to have a “Bonnie and Clyde” type of union between apo(a) and an apoB-100 particle.  And apo(a) has a “type,” and he tends to prefer “small LDL particles.”  He doesn’t want to marry Big Buoyant Bonnies, which are much more prevalent in FCS.  So if there is a relative shortage of small apoB-100 particles to be apo(a)’s Partner in Crime, this would necessarily decrease the production rate.  It’s plausible!

And one more thing for the 3 people still reading this…there are studies LIKE THIS ONE showing a decrease in Lp(a) levels in those who adopt a Low-Carb Ketogenic Diet (LCKD).  If the reason for the drop in Lp(a) is, in fact, a reduced area under the curve of LPL-dependent lipolysis decreasing Lp(a) synthesis (along with a shift to larger, buoyant apoB-100 species), then this would fall in line with the mechanistic model proposed in THIS ARTICLE for lipid trafficking in low-carbohydrate states.  Other models?  I’m not so sure.

And it’s possible I may be Bob Barker-ing up the wrong tree here with my speculations, but I, for one, found the unexpected showdown between chylomicrons and Lp(a) in this article quite memorable!