Team determines how cholesterol moves inside cells
The researchers found that high-density lipoprotein, or HDL, sometimes referred to as “good” cholesterol, is transported from the outer wall to the interior of cells by a protein that helps create a “bridge” between the two areas.
HDL cholesterol has been linked for years to a reduced risk of coronary heart disease. Recent studies, however, have raised questions about how it actually affects heart risk, suggesting that how HDL cholesterol circulates, rather than its concentration, may have more to do with disease risk. In this study, the researchers set out to determine how HDL cholesterol moves from the cell’s outer membrane to areas inside the cell, which had previously been a mystery.
The researchers suspected that proteins called Asters might be responsible for carrying HDL cholesterol from the cell membrane to the interior of the cell. Asters are tethered to a structure inside the cell called the endoplasmic reticulum, a network of membranes inside the cell. The team first isolated the region of the Asters most likely to bind cholesterol, and found that the Asters did bind. The region also efficiently transferred cholesterol molecules between two artificial membranes in a test tube.
The team also studied mice lacking one of the three Asters, and confirmed that it is required for HDL movement from the cell membrane into the endoplasmic reticulum in the adrenal gland, which uses cholesterol to make steroid hormones such as cortisol.
Understanding how cholesterol is transported into cells may lead to new ways to diagnose and treat high cholesterol and other blood lipid disorders in humans. Altered cholesterol metabolism is linked to sometimes-fatal diseases including coronary heart disease. This study may help pave the way for new diagnostic and therapeutic tools for these diseases.
Dr. Peter Totonoz, a professor of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA, and Jaspreet Sandhu, a student in pathology and laboratory medicine, are the study’s senior author and first author, respectively. Other UCLA-affiliated authors are Xu Xiao, Thomas Weston, Alessandra Ferrari, Jose Orozco, David Strugatsky, Stephen Lee, Cuiwen He, Cynthia Hong, Laurent Bentolila, and Stephen Young. Non-UCLA authors are Shiqian Li, Louise Fairall, Simon Pfisterer, Jennifer Gurnett, Dipti Vashi, Celine Hartman, Haibo Jiang, Alberto Gatta, Tim Levine, Annie Ferng, Richard Lee, David Ford, Elina Ikonen and John Schwabe.
The study was published in the journal Cell.
This work was funded by National Institutes of Health grants; a P. Whitcome Fellowship; the Academy of Finland; the Sigrid Juselius Foundation; and the Helsinki Institute of Life Science Imaging Unit and Biomedicum Functional Genomics Unit, both at the University of Helsinki.