In people with a rare genetic condition, great globs of low-density lipoprotein (LDL) build up in the blood, thickly coat arteries, and break off in chunks to cause frequent heart attacks—all before puberty.
In people with less severe forms of high LDL cholesterol, the inelegant and greasy buildup ultimately may come from a simple shift of a protein loop deep inside the cell. The chain of events that nudges a string of six tiny amino acids out of reach of its molecular teammate is enough to disrupt the efficient cellular machinery that retrieves cholesterol from the blood.
“When you get to the end, it’s something that’s really really small,” Michael Brown told an HMS audience in an April 1 talk.
Still active in the lab, Brown summed up 37 years of LDL research at this year’s seminar for the annual HMS MD–PhD lecture series, “Leaders in Biomedicine.” Brown and his research partner Joseph Goldstein won the 1985 Nobel Prize in Physiology or Medicine for discovering LDL receptors and working out their molecular pathway.
Brown and Goldstein started with what they knew: the pivotal enzyme in cholesterol biosynthesis (now targeted by statin drugs.) The enzyme was up in normal cultured skin cells and went down when cholesterol was added to the dish. But skin cells of people with familial hypercholesterolemia never shut off the enzyme.
The team, based at the University of Texas Southwestern Medical School in Dallas, identified LDL receptors, showed they carried cholesterol into cells and found that receptor numbers rose and fell in concert with changes in cholesterol levels within the cell. Cellular production of cholesterol rose or shut down in inverse proportion to low or high cellular levels of cholesterol.
People with familial hypercholesterolemia have a primary defect in the gene encoding LDL receptors, they found. In the most severe form of the disease, LDL receptors are completely absent, allowing LDL to build up to very high levels in the blood and causing heart attacks in affected children as young as 18 months.
More recently, the two labs have traced the finely tuned feedback system down to its molecular roots. They have learned precisely how cholesterol in the cellular membranes communicates with the nucleus to turn regulatory genes and enzymes on and off.
Brown credited a combination of medical and scientific training for sparking their scientific quest. It began when he and Goldstein first observed a girl, 6, hospitalized for heart attacks caused by familial hypercholesterolemia. Brown and Goldstein had met during their internships and residencies at Massachusetts General Hospital. The two were doing their postdoctoral training in enzyme biochemistry in neighboring labs at the National Institutes of Health when they observed the girl whose dire medical condition inspired their research into LDL metabolism.
Brown titled his talk, “Why Cholesterol?” The program guide quoted his explanation of the title. “In 1972, Joe Goldstein and I were eager young physician-scientists…. We decided to form a partnership to attack a genetic disease that causes high blood cholesterol and heart attacks. Our more sophisticated friends chose sexier problems like cancer, developmental biology and neuroscience. They asked: ‘Why cholesterol?’”
