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 a-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 20% of the HDL molecule, and to truly understand the story of HDL, we need to broaden our focus. The latest iteration of this fascinating tale, presented in this issue of Diabetes by Tan et al. (7), does exactly that. The HDL particle appears to serve a myriad of functions besides reverse cholesterol transport. The well-recognized anti-inflammatory effect has been postulated to play an important role in the pathogenesis of various conditions including obesity, fatty liver disease, diabetes, dementia, osteoporosis, and chronic obstructive lung disease (8). It also affects multiple steps in the response to sepsis including endotoxin release and clearance and response by the macrophages and endothelial cells (9). Similarly, it influences endothelial cell differentiation and function, including nitric oxide production, and may have cytoprotective and wound healing effects (10). All these functions assume special significance in populations with diabetes mellitus (DM) who are known to have endothelial dysfunction, microand macrovascular disease, and poor wound healing. Although there has been considerable research on the nature of dyslipidemia in DM characterized by high triglycerides and low HDL-C, as well as its effect on atherosclerosis, relatively less information is available about the role of HDL function in the pathogenesis of other complications in DM. In a series of elegant experiments, Tan et al. (7) demonstrate the ability of reconstituted HDL (rHDL) to overcome diabetes-impaired angiogenesis and wound healing. Using a murine hind limb ischemia model, they showed that impaired neovascularization in streptozotocin-induced DM mice was significantly ameliorated by daily infusions of rHDL containing human apolipoprotein A-I (Apo A-I) and a phospholipid. Similarly, topical application of rHDL was shown to improve wound healing. These actions were not noticed in mice without the HDL receptor scavenger receptor class B type 1, thus demonstrating the need for the lipoprotein–receptor interaction. Further, in vitro studies using human coronary endothelial cells helped identify possible mediators and mechanisms of action. High glucose concentrations impair stability of hypoxia-inducible factor1a, the pivotal transcription factor mediating ischemiainduced revascularization, in addition to decreasing the production and signaling of vascular endothelial growth factors. By decreasing prolyl hydroxylase expression, likely mediated by increased expression of the E3 ubiquitin ligases, rHDL is able to restore hypoxia-inducible factor-1a stability and vascular endothelial growth factor signaling (Fig. 8 in Tan et al. [7]). All these effects were independent of glucose and lipid concentrations. These observations are quite intriguing and seem to suggest that the effects of rHDL may not be secondary to cholesterol transport but a direct consequence of the signaling cascade initiated by Apo A-I scavenger receptor class B type 1 interaction. Further elucidation of this molecular map should help identify other