I’ve previously written about APOC3, the “Great Inhibitor” of lipoprotein lipase (LPL) HERE as well as the Hot Mess of the ANGPTL family HERE, so before you take the plunge into this topic, I’d recommend checking out those articles!
Basically, people who lack APOC3 and/or ANGPTL3 are more efficient at clearing lipoprotein particles. Recall, a primary function of lipoproteins is to deliver triglyceride cargo to target tissues before returning to the liver for clearance. Lipoproteins are MAILMEN, and after they deliver the mail (via LPL-mediated triglyceride lipolysis), we want them to return home (the liver) at the end of the day rather than drive their trucks into your arterial wall. VLDL particles are mailmen who work around the clock, and after delivering some of their cargo they eventually become LDL particles. ApoB-48 chylomicrons are mailmen who work the shift after you eat. And predictably, INSULIN is an important hormonal regulator of both ApoC3 and ANGPTL3.
So that sets the stage for this chart, which highlights some of the key differences in people with genetic loss-of-function (LOF) of either APOC3 or ANGPTL3.
| Lipid Measurement | APOC3 LOF vs Control | ANGPTL3 LOF vs Control |
| Triglycerides | 57% lower | No difference |
| VLDL1 Secretion | No difference | No difference |
| VLDL1 Clearance | 2x higher | 4x higher |
| ApoB-48 secretion | No difference | No difference |
| ApoB-48 clearance | 280% higher | 70% higher |
Additionally, the transit time from a VLDL to becoming an LDL particle is normally almost 18 hours in typical subjects. However, in folks with APOC3 LOF or ANGPTL3 LOF, this time is reduced to 4.3 and 5.1 hours, respectively. This means there is more efficient lipolysis (delivery of the triglyceride cargo). The mailmen are highly industrious!
And then, since the mailmen are highly efficient at delivering the triglyceride mail, the CLEARANCE of VLDL (mailmen who work around the clock) and ApoB-48 particles (mailmen who work the postprandial shift) is enhanced. After delivering the mail, the mailmen go home to the liver at the end of the day. That’s the kind of workforce we want…no remnant particles loitering and causing mischief!
Another key takeaway from this chart is that there is no impairment in SECRETION of VLDL or ApoB-48 particles. This is critical, as impaired lipoprotein secretion will result in fatty liver (as seen in other states of familial hypobetalipoproteinemia and with medications such as Lomitapide). If stacks of triglyceride mail are accumulating in the liver because the mailmen aren’t getting out there to deliver the cargo, then steatosis can result.
This is pretty cool, but these are incredibly small sample sizes in these kinetic studies. So for the Small Sample Size of people who are also excited about this, let’s pump the brakes a little bit and try to temper our enthusiasm. But there is one more thing that’s even crazier…there were several people with ANGPTL3 HOMOZYGOUS loss-of-function. And those folks had a 16x higher VLDL1 clearance, a 620% increased ApoB-48 clearance, and the transit time from VLDL to LDL was reduced to 67 minutes!
Interestingly, ANGPTL3 LOF folks also had higher levels of ketones and lactate in THIS STUDY, and there are a few parallels from these findings to the Lipid Energy Model (and just like that, everyone from all tribes of Lipid Land instantly shifted toward Fight Mode)! However, there are also important differences unexplained by the Lipid Energy Model, so stay tuned for our upcoming paper that we feel more completely elucidates the physiologic phenomena resulting in ketogenic diet-induced hypercholesterolemia.
So you guys all have A LOT to look forward to, as much of what I described here is currently unpublished as well! May your Mailmen be efficient as you patiently wait for these full publications, but for now you can enjoy THIS ARTICLE for more on this fascinating topic!
