When we eat too many calories—especially from sugar, fats, alcohol, or carbs—the body stores the extra energy as fat called triglycerides. These fats are packed away in fat cells to be used later, like a fuel reserve.
But when there’s too much fat in the blood, it can become dangerous. This condition is called hypertriglyceridemia, and it raises the risk of heart attacks, strokes, and a painful illness called pancreatitis.
Doctors usually tell people to eat healthier and exercise more to control their triglycerides. In more serious cases, patients are given medication. But creating the right drug has been tricky because fat regulation in the body is complex.
It depends on a balance between fat released from the liver and intestines and how fast it’s broken down and cleared from the blood. When the body makes more fat than it can clear, problems start to build up.
Scientists have long known about a protein in the body called Liver X Receptor (LXR), which controls many genes related to fat and cholesterol.
When LXR is active, levels of triglycerides and cholesterol go up. So, blocking LXR could be a helpful strategy to reduce blood fat. But LXR is also important in other parts of the body—especially for moving cholesterol out of the arteries—so blocking it everywhere could cause more harm than good.
Now, scientists at EPFL in Switzerland and OrsoBio have developed a new drug that may solve this problem. The drug is called TLC‑2716. What’s special about it is that it targets LXR only in the liver and gut, not in the rest of the body. This way, it lowers triglycerides without affecting helpful cholesterol processes in other organs.
The drug works in a special way. Instead of just blocking LXR, it flips its signal to do the opposite of what it normally does. That makes it even more powerful in lowering fat levels. This kind of drug is called an inverse agonist.
To find the right target, the scientists first looked at huge sets of human genetic data. They searched for variations of LXR linked to high triglyceride levels. They found a strong connection with a version of LXR called LXRα, which is mainly active in the liver. This confirmed their idea that blocking LXRα could help reduce blood fats.
Next, the scientists tested the new drug in animals with high fat levels. It worked: TLC‑2716 lowered triglycerides, reduced cholesterol, and even helped clear fat from the liver. The same effects were seen in human lab-grown mini-livers, with less fat buildup and less inflammation.
Safety is a big concern in drug development. Tests in mice and primates showed that TLC‑2716 stays mostly in the liver and gut. This helps avoid unwanted side effects elsewhere in the body. Once the safety results looked good, the team moved on to testing the drug in people.
In a small clinical trial, healthy adults took the drug for 14 days. The study was mainly to check if the drug was safe, and it passed that test. But the researchers also saw promising effects.
At higher doses, participants had big drops in their triglyceride levels—up to 38.5%. Another type of harmful fat, called remnant cholesterol, dropped by as much as 61%. And this happened even though the people in the trial started out with normal fat levels and weren’t taking any other medications.
The drug also helped the body clear fats faster by lowering the activity of two proteins, ApoC3 and ANGPTL3, which normally slow down fat removal. At the same time, the drug didn’t interfere with genes needed for cholesterol cleanup elsewhere in the body.
These results show that TLC‑2716 may offer a new way to treat high triglycerides and related health problems. By targeting just the liver and gut, the drug avoids the side effects that have stopped similar treatments in the past.
The trial was short and small, so bigger studies will be needed to confirm the results. But the findings are exciting.
They show for the first time in humans that dialing down LXR in just the right places can lower harmful fats without damaging helpful cholesterol pathways. The next step is to test the drug in people who already have high triglycerides or liver problems.
This research marks a big step toward safer, smarter ways to treat serious fat-related health problems.
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The study is published in Nature Medicine.
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