I’ve mentioned APOC3 and APOC3-lowering therapies such as Olezarsen and Plozasiran previously, but there is potentially a NEW LXR-BASED ELIXIR for folks with high triglycerides…and perhaps even for metabolic-associated steatohepatitis (MASH).

So what is LXR?  Well, it’s essentially a STEROL SENSOR, and the following summary will be sponsored by the Letter X!

Since cellular cholesterol content is very tightly regulated, when sterol levels get high, LXR upregulates genes that will help eXport the cholesterol cargo elsewhere.  Enzymatic and non-enzymatic modification of cholesterol results in the formation of oXysterols.  Oxysterol levels tend to rise when intracellular sterol levels rise, and these oxysterols activate LXR, which works with its heterodimer partner Retinoid X Receptor (RXR) to eXcommunicate eXcess lipids.  Some of the target genes of LXR are ABCA1, ABCG1, and ABCG5/8, which will be familiar efflux transporters for the Lipid Geeks reading this article.

And there are two isoforms of LXR: alpha and beta.  Although both isoforms are expressed rather ubiquitously, for our purposes here, LXR alpha is predominant in the liver, whereas LXR beta serves a prominent role in the BRAIN.  In fact, LXR agonism in the central nervous system of rodents seems to beneficially clear amyloid and mitigate Alzheimer’s Disease pathology!

So why don’t we just activate LXR across the board since we don’t want cholesterol accumulating and since we don’t want to get Alzheimer’s Disease?

Well, the tricky thing about LXR agonism is that historically, it SENDS TRIGLYCERIDES THROUGH THE ROOF.  You probably won’t live long enough to avoid Alzheimer’s if you’re having pancreatitis every other day.

Ok, so why don’t we just inhibit LXR?

Well, LXR is pretty important in macrophages and reverse cholesterol transport.  We would like LXR to help our macrophage clean-up crew effectively dispatch of sterol criminals, but if LXR is inhibited, then we may end up with atherosclerotic messes.

The trick seems to be downregulating LXR in JUST THE LIVER (and intestine) when it comes to reducing triglycerides, since LXR activates genes associated with de novo lipogenesis, including SREBP1-c and Fatty Acid Synthase.  And this happens to be what they have achieved in THIS ARTICLE with a liver-specific LXR inverse agonist.  (An inverse agonist isn’t technically an antagonist, but does work to downregulate LXR activity).

The Phase 1 studies showed a decrease in triglycerides of 38.5% in a small human cohort which rose to >60% when participants had baseline triglycerides >100 mg/dL.  Additionally, a Phase 2 study showed a decrease in liver fat after only 4 weeks!  (Others in the hypertriglyceridemia market will likely raise at least one eyebrow at this finding).

So will this LXR-based elixir decrease triglyceride gravy and help people who are shaped like potatoes cure their MASH?  Stay tuned!