HDLs extract lipophilic drugs from cells

High-density lipoproteins (HDLs) prevent cell death induced by a variety of cytotoxic drugs. The underlying mechanisms are however still poorly understood. Here we present evidence that HDLs efficiently protect cells against thapsigargin (a SERCA inhibitor) by extracting the drug from cells. Drug efflux could also be triggered to some extent by low-density lipoproteins (LDLs) and serum, which contains lipoproteins. HDLs did not reverse the non-lethal mild endoplasmic reticulum (ER) stress response induced by low thapsigargin concentrations or by SERCA knock-down but HDLs inhibited the toxic SERCA-independent effects mediated by high thapsigargin concentrations. HDLs were also found to extract other lipophilic compounds, such as the anti-diabetic drug glibenclamide. In contrast, hydrophilic substances (doxorubicin hydrochloride, rhodamine 123) were not extracted from cells by HDLs. This work shows that HDLs utilize their capacity of loading themselves with lipophilic compounds, akin to their ability to extract cellular cholesterol, to reduce the cell content of hydrophobic drugs. Silencing of the P-glycoprotein/ABCB1 transporter reduced the capacity of cells to load thapsigargin on HDLs. This work suggests that HDL-mediated cell efflux of toxic lipophilic xenobiotic is beneficial but also that HDL-mediated efflux can be detrimental to the therapeutic benefit of lipophilic drugs such as glibenclamide. Lipoprotein-mediated drug efflux should therefore be considered when evaluating drug efficacy.