Common antidepressants may help lower a stubborn, disease-causing form of cholesterol by boosting liver cells’ ability to absorb it from the bloodstream, a finding that could offer a dual-purpose approach to treating depression and reducing heart-disease risk. The results, published in the Journal of Lipid Research, emerge from laboratory experiments conducted by researchers at the University of Otago and the University of New South Wales, led by Nikita Deo, Sally P. A. McCormick and Gregory M. I. Redpath.
lipoprotein(a) is a complex blood particle that ferries fats and cholesterol around the body. It resembles low-density lipoprotein, or “bad cholesterol,” but carries an extra protein called apolipoprotein(a), making it particularly prone to causing arterial blockages. High levels are largely genetic and affect about a fifth of people of European descent.
Traditional cholesterol-lowering drugs, such as statins, do not reduce lipoprotein(a) levels, leaving a major gap in preventing cardiovascular disease for many patients. Researchers are therefore focused on understanding how the body clears this molecule from circulation.
Cells take up external substances through endocytosis, a process in which the cell membrane folds inward to swallow material. A specific form called macropinocytosis — sometimes described as cellular drinking — handles the uptake of lipoprotein(a). In this process, the cell membrane protrudes outward to engulf surrounding fluid and particles.
The Otago and UNSW team sought to map how cellular drinking operates in liver cells and to identify what cues stimulate uptake of lipoprotein(a).
In the initial experiments, researchers treated human liver cells grown in culture with the older antidepressant imipramine, a tricyclic drug previously identified as a blocker of cellular drinking in some lab studies. After overnight treatment, they introduced lipoprotein(a) into the surrounding fluid and observed uptake.
The surprising result was that imipramine did not block the process; instead, the liver cells absorbed nearly three times as much lipoprotein(a). The researchers confirmed this effect was specific to lipoprotein(a) by testing regular “bad cholesterol,” which was not influenced by the drug.
Following this, the team explored whether newer antidepressants commonly prescribed for depression would have a similar effect. They tested citalopram, sertraline and fluoxetine, with paroxetine included in later experiments. Citalopram increased uptake to a level comparable with imipramine, while sertraline and fluoxetine showed no change; paroxetine also boosted absorption.
To understand how imipramine and citalopram produced the effect, the scientists examined the liver cell surface where lipoprotein(a) must bind before internalisation. By cooling the cells to pause uptake, adding lipoprotein(a), and using fluorescent tags, they found that imipramine and serotonin roughly doubled the amount of lipoprotein(a) that attached to the cell surface.
The study noted that these drugs did not alter the cells’ ability to bind a control sugar molecule, suggesting the effect was specific to lipoprotein(a).
The researchers hypothesised that increasing extracellular serotonin — a consequence of antidepressant action — might drive the enhanced surface binding. Indeed, adding pure serotonin to the cell cultures overnight produced the same outcome as the medications, increasing both surface binding and eventual uptake of lipoprotein(a).
When considering why sertraline did not boost uptake despite being in the same class, the team pointed to dynamin, a protein involved in pinching off the internalised pouches. Sertraline is known to interfere with dynamin, potentially preventing the uptake process from proceeding for certain molecules. Tests using a control molecule that requires dynamin for entry supported this explanation.
The study also examined receptor dynamics on the liver cell surface. Imipramine and serotonin increased the presence of a receptor that binds lipoprotein(a), while citalopram did not raise receptor levels but did increase an accessory protein involved in the swallowing process. The exact mechanism linking citalopram, serotonin and this accessory protein requires further mapping.
Tracking the fate of lipoprotein(a) after uptake showed that cells treated with imipramine and citalopram directed the particles toward recycling compartments. The authors suggest the recycling process could strip the harmful lipid component from the particle before returning the harmless protein portion to the bloodstream, potentially lowering cardiovascular risk.
However, the researchers emphasise that the work was conducted exclusively with isolated cells in a laboratory setting. The liver interacts with multiple tissues and signals in a living body, and the study notes that the citalopram concentration used exceeded typical human dosing. Serotonin levels tested were also higher than normal biological conditions. Further animal studies and human trials are necessary to determine safety and effectiveness in patients.
Nevertheless, the authors conclude that some depression patients, who often have elevated lipoprotein(a), might benefit from existing, affordable medications that could simultaneously address mood and cardiovascular risk. The study is titled Antidepressants stimulate lipoprotein(a) macropinocytosis via serotonin-enhanced cell surface binding, and was authored by Deo, Siddiqui, Peppercorn, Madani, Rutherford-Blyth, Rutledge, Williams, McCormick and Redpath.
