When we eat, our body converts excess calories, especially carbohydrates, sugar, fats and alcohol, into molecules called “triglycerides.” It is a form of fat or lipid, which the body stores in its fat cells as energy fuel between meals.
However, excess fat in the body can be dangerous, causing a condition called “hypertriglyceridemia” (meaning excess triglycerides in the blood). This significantly increases the risk of heart disease, stroke and pancreatitis. This is why it is generally advisable to adopt a healthy lifestyle in terms of diet and exercise, while severe cases require drug treatment.
Controlling the level of lipids in the blood relies on a careful balance. The liver and intestine release fat particles into the bloodstream, while enzymes break them down and remove them. One of the main regulators of this system is a protein called Liver X Receptor, or LXR, which controls several genes involved in making and metabolizing fat.
When LXR is active, triglycerides and cholesterol tend to increase. Decreasing LXR activity with drugs seems promising, but because the receptor is also involved in other cholesterol-protecting pathways in the body, blocking it everywhere could do more harm than good. This dilemma has held back progress in the field for years.
A team, led by Johan Auwerx of EPFL and Mani Subramanian of OrsoBio, addressed this problem with an orally administered compound capable of repressing LXR activity, particularly in the liver and intestine, to reduce triglycerides without disrupting protective cholesterol pathways in the body.
Reduces fat without collateral damage
The compound TLC‐2716 is what is called an “inverse agonist” of LXR. Unlike a “blocker” (antagonist), which simply prevents a receptor from activating, an “inverse agonist” causes the receptor to send a signal opposite of what it would normally send.
Scientists began by analyzing large human genetic data sets to determine which LXR variant is linked to biomarkers of elevated triglycerides in the blood. The data highlighted genetic variants within LXRα, which is highly expressed in the liver. Further research helped select TLC‐2716 as an effective compound for testing LXRα.
The researchers then moved from the computer to the laboratory. In rodent models of metabolic disease, TLC‐2716 and a related compound reduced blood triglycerides and cholesterol and decreased fat accumulation in the liver. Meanwhile, experiments in human liver organoids (laboratory-grown miniature models of diseased liver tissue) showed the same trend, with less lipid accumulation and less inflammation and fibrosis.
Next step: security. Toxicological studies in mice and nonhuman primates, combined with pharmacokinetic analyses, have shown that TLC‐2716 remains largely in the liver and intestine. This is essential because it limits exposure to other tissues where LXR inhibition could be risky, thereby solving the main problem in drug development to treat metabolic diseases linked to high triglycerides in the body.
The laboratory results paved the way for a randomized, placebo-controlled Phase 1 study in healthy adults. Participants were administered TLC‐2716 for 14 days, at a single dose per day. The trial initially focused on safety and tolerability, and the authors say the drug met primary endpoints.
Strong reduction in cholesterol
Even this short-term trial had clear effects: Participants who received higher doses of TLC‐2716 showed notable drops in triglycerides as well as residual cholesterol. At the highest doses of TLC‐2716 (12 mg), triglycerides decreased by up to 38.5%, while residual postprandial (after meals) cholesterol fell by up to 61%. This occurred even though the participants started with relatively normal lipid levels and were not taking other lipid-lowering medications.
The treatment also accelerated the elimination of triglycerides by reducing the activity of two proteins that normally slow it down, ApoC3 and ANGPTL3. At the same time, the assay did not detect a decrease in the cellular expression of the ABCA1 and ABCG1 genes, used here as markers linked to reverse cholesterol transport.
The trial results show that selective reduction of LXR activity in the liver and intestine by the compound TLC‐2716 could offer a new way, complementary to other approaches, to combat high triglyceride levels and associated metabolic disorders. Phase 1 data supports continued clinical trials in Phase 2 studies, including in individuals with hypertriglyceridemia and MASLD. Larger-scale trials will be needed, but, for now, the concept has proven itself for use in humans.
The study, published in Nature Medicine, is the first of its kind to have been carried out on humans.
