HDL Cholesterol Story Is Dead: Long Live HDL!

It is a great irony that the earliest discovered lipoprotein is also the least well understood. In 1929, Michel Machebouef at the Pasteur Institute in Paris, using salt precipitation techniques, isolated a lipoprotein particle from horse serum composed predominantly of an α-globulin (59%), which we now know to be high-density lipoprotein (HDL) (1). Epidemiological studies in the 1970s, including the Framingham Heart Study, established the strong inverse relationship between HDL cholesterol concentration (HDL-C) and both the incidence and prevalence of coronary artery disease (2,3). The resulting belief about the cardioprotective effects of high HDL-C led to many therapeutic efforts to raise HDL-C using pharmaceutical agents such as niacin, fibrates, and cholesterol ester transfer protein inhibitors that have been largely disappointing (4,5). This has led to a shift in focus from HDL-C to assessment of HDL function, primarily its role in reverse cholesterol transport (4). As many experts have stressed (5), the cholesterol in HDL does not (and cannot) protect, but this does not necessarily reflect on its functional intricacies and importance. Recent evidence does indeed support this greater emphasis on HDL functionality (6) to assess risk for major cardiovascular events, but even this would be a narrow focus. Cholesterol constitutes less than …