According to research reviewed by Gram, betulinic acid, a plant compound, reduced PCSK9, a protein that blocks the liver from removing LDL cholesterol, even when statins were present in liver cell and mouse experiments. In high-fat diet mice, it also further lowered LDL cholesterol alongside atorvastatin. These results are early and not yet proven in people.
Statins are common cholesterol medicines, but they can trigger the liver to make more of a protein called PCSK9, which blocks the liver from removing LDL (“bad”) cholesterol from the blood. A new study in Phytotherapy Research, published in 2026, tested whether betulinic acid, a compound found in birch bark and some other plants, could counter this effect. In liver cell experiments and in mice fed a high-fat diet, betulinic acid lowered PCSK9 levels, both on its own and alongside the statin atorvastatin. The mice also had lower LDL cholesterol when the compound was added to the statin. According to research reviewed by Gram, these results are promising, but they come from cells and animals, so it is too early to know whether people would benefit.
Key Statistics
A 2026 study published in Phytotherapy Research tested betulinic acid in two human liver cell lines and in high-fat diet-fed mice, and found it reduced PCSK9 levels both with and without the statin atorvastatin.
In the 2026 study, betulinic acid kept or increased LDL receptor levels in both liver cell lines while lowering PCSK9, which is the protein that normally breaks down those receptors.
The Quick Take
- What they studied: Can betulinic acid, a plant compound, reduce a protein that rises during statin treatment and limits how well statins lower cholesterol?
- Who participated: The study used two types of human liver cells grown in lab dishes and mice fed a high-fat diet. The exact number of mice was not clearly reported in the available summary, so the sample size is unknown.
- Key finding: Betulinic acid reduced PCSK9 levels in liver cells, both alone and with the statin atorvastatin, while keeping LDL receptors (the parts of liver cells that pull cholesterol out of the blood) at the same or higher levels. In mice, it also further lowered LDL cholesterol during statin treatment.
- What it means for you: This is early laboratory and animal research. It does not show that betulinic acid is safe or helpful for people. If you take a statin, keep taking it as prescribed and talk with your doctor before trying any supplement.
The Research Details
The researchers first worked with two liver cell lines, called HepG2 and Huh7. These are cells that grow in lab dishes and behave in some ways like real liver cells. They added betulinic acid with or without atorvastatin, then measured how much PCSK9 the cells made and released, using lab tests that count proteins and genetic messages.
Next, the team tried to find out how betulinic acid works inside the cells. They looked at which genes turned on or off, and they blocked or boosted a receptor called FXR, which acts like a switch that controls many genes involved in cholesterol and bile acid balance. They also used tiny genetic tools to reduce levels of FXR or a related protein called SHP. When these switches were weakened, betulinic acid lost much of its effect on PCSK9 and LDL receptors.
Finally, the researchers fed mice a high-fat diet and gave them betulinic acid, atorvastatin, or both. They measured PCSK9 in the blood and liver and checked LDL cholesterol levels in the blood. Animal studies like this help scientists see how a treatment behaves in a whole body before considering human trials.
Using both cell experiments and animal studies lets researchers test an idea step by step. The cell work shows what the compound does at the molecular level, and the mouse work checks whether those effects appear in a living animal with a fatty-diet metabolism. Blocking and boosting the FXR and SHP switches helped the team show that these pathways are truly involved, rather than the effect being a side result.
The study used several complementary methods, and the researchers tested their findings more than one way, which adds confidence. The journal is a respected specialty publication in plant-based medicine. However, the study has not been replicated by other labs in the available information, the exact number of animals was not clearly reported, and lab and animal results often do not carry over to people. Readers should treat the findings as a starting point for further research.
What the Results Show
The main result was that betulinic acid lowered PCSK9 in both liver cell lines. PCSK9 is a protein that tags LDL receptors for destruction, so fewer LDL receptors remain on liver cells to pull cholesterol from the blood. Statins raise LDL receptor levels, but they also raise PCSK9, which can partly cancel out the benefit. In this study, betulinic acid reduced PCSK9 even when atorvastatin was present.
Importantly, the compound did not lower LDL receptors in these cells. It kept them at the same level or increased them. This matters because a PCSK9 drop that also lowered receptors would not help cholesterol removal. The researchers also found changes in several genes that control bile acid production. Betulinic acid raised levels of SHP and SLC51B and lowered CYP7A1 and CYP8B1, which are involved in turning cholesterol into bile acids.
The mechanism appeared to depend on the FXR and SHP switches. When these were weakened with genetic tools or drugs, the effects of betulinic acid on PCSK9 and LDL receptors were reduced. The team also observed that betulinic acid increased SHP linked to SREBP2, a protein that controls cholesterol-making genes, without greatly reducing SREBP2 itself. This suggests the compound may tune the system rather than simply shut it down.
In high-fat diet mice, betulinic acid reduced PCSK9 in both blood and liver. When combined with atorvastatin, it further lowered blood LDL cholesterol compared with the statin alone. These animal results are consistent with the cell findings, but they do not tell us how large the effect would be in people.
The researchers reported that betulinic acid reduced PCSK9 secretion, meaning less of the protein was released from liver cells into the surrounding fluid. This is relevant because PCSK9 circulates in the blood, where it can act on liver cells throughout the body. The changes in bile acid genes suggest that the compound may also influence how the liver handles fats and bile, a topic that deserves further study.
Earlier research had reported that betulinic acid lowers basal PCSK9 levels, meaning PCSK9 when no statin is present. This study extends that work by testing the compound during statin treatment, which is the situation where PCSK9 rises and limits the statin’s effect. Other PCSK9-lowering approaches, such as PCSK9 inhibitor injections, have been studied in large human trials. Betulinic acid is at a much earlier stage, so it cannot yet be compared directly with those treatments for safety or effectiveness.
Most of the evidence comes from lab-grown cells and mice, which do not fully match human biology. The study does not report how long the treatment lasted in mice or how much betulinic acid was given in a form that people could use. The exact number of animals was not clearly stated in the available summary, which makes it harder to judge how strong the animal results are. No human participants were studied, so there is no information about safety, side effects, or whether lower PCSK9 would lead to fewer heart problems. The findings also need to be repeated by independent researchers.
The Bottom Line
Based on this single early-stage study, the strongest conclusion is that betulinic acid is worth further research as a possible add-on to statin treatment. Confidence that it helps people is currently low, because no human trials have been reported. Anyone taking a statin should continue prescribed treatment, and any decision to add a supplement should be made with a doctor who knows the full medical history.
Researchers studying cholesterol, statin treatment, and plant-based compounds should pay close attention, as should people with high LDL cholesterol who are curious about future options. People who take statins should discuss the research with their doctor rather than changing medicines on their own. People who are pregnant, nursing, taking other medicines, or managing liver or kidney disease should be especially careful about any supplement and should check with a healthcare professional first.
Lab and animal findings like these usually take several years to reach human testing, and many compounds that work in animals never prove useful or safe in people. If betulinic acid moves into human trials, researchers would need to test safety, the right dose, and whether it actually lowers heart risk. Realistically, any clinical use is likely many years away.
Frequently Asked Questions
Can betulinic acid help statins lower cholesterol better?
Early research suggests it might. A 2026 study in Phytotherapy Research found that betulinic acid reduced PCSK9, a protein that limits statin effectiveness, and further lowered LDL cholesterol in high-fat diet mice. These results have not been tested in people, so benefits for humans remain unknown.
What is PCSK9 and why does it matter for cholesterol?
PCSK9 is a protein made mostly by the liver that marks LDL receptors for destruction. Fewer receptors means less LDL cholesterol gets pulled from the blood. Statins can raise PCSK9 as a side effect, which may partly offset their cholesterol-lowering benefit.
Is betulinic acid safe to take with a statin?
Safety in people has not been established. The 2026 study tested betulinic acid only in liver cells and mice. Anyone taking a statin should speak with a doctor or pharmacist before adding any supplement, because interactions and side effects are not yet known.
Where does betulinic acid come from?
Betulinic acid is a natural compound found in the bark of birch trees and in some other plants. Researchers have studied it for several health effects in the lab. Its presence in a plant does not mean that eating or taking plant products will produce the effects seen in this study.
Want to Apply This Research?
- Log your statin dose and timing daily, and record any new supplements with their dose. Also store your LDL cholesterol results from each blood test, noting the date, so you can see how your numbers change over time.
- Use the app to set reminders for your prescribed statin and to schedule regular lipid panel blood tests with your doctor. Before adding any new supplement, use the app to write a question for your doctor, such as whether it could interact with your medicines.
- Track LDL cholesterol through regular blood tests, usually every few months as your doctor advises, and review the trend with your healthcare team. Keep notes on diet, exercise, and any side effects. Over the long term, your doctor’s measurements matter more than any single app entry, and the app should help you prepare for those conversations.
This article summarizes early laboratory and animal research and is for general information only. It is not medical advice. The study has not been tested in humans, so its results should not be used to start, stop, or change any medicine or supplement. Anyone taking a statin or managing high cholesterol should consult a qualified healthcare professional before making changes.
This research translation is published by Gram Research, the science division of Gram, an AI-powered nutrition tracking app.