High Density Lipoproteins: From Biological Understanding to Clinical Exploitation

Abstract

In both epidemiological and clinical studies as well as the meta-analyses thereof, low plasma levels of high-density lipoprotein (HDL) cholesterol (HDL-C) identified individuals at increased risk of major coronary events. Observational studies also found inverse associations between HDL-C and risks of ischemic stroke, diabetes mellitus type 2, and various cancers. In addition, HDLs exert many effects in vitro and in vivo which protect the organism from chemical or biological harm and thereby may interfere with the pathogenesis of atherosclerosis, diabetes, and cancer but also other inflammatory diseases. Moreover, in several

animal models transgenic overexpression or exogenous application of apolipopro- tein Α-I (apoA-I), the most abundant protein of HDL, decreased or prevented the

development of atherosclerosis, glucose intolerance, or tissue damage induced by ischemia or mechanical injury. However, as yet drugs increasing HDL-C such as fibrates, niacin, or inhibitors of cholesteryl ester transfer protein have failed to consistently and significantly reduce the risk of major cardiovascular events, especially when combined with statins. Moreover, mutations in several human genes as well as targeting of several murine genes were found to modulate HDL-C levels without changing cardiovascular risk and atherosclerotic plaque load, respectively, into the opposite direction as expected from the inverse correlation of HDL-C levels and cardiovascular risk in epidemiological studies. Because of these controversial data, the pathogenic role, and, hence, the suitability of HDL as a therapeutic target, has been increasingly

questioned. Because of the frequent confounding of low HDL-C with hypertrigly- ceridemia, it has been argued that low HDL-C is an innocent bystander of (post- prandial) hypertriglyceridemia or another culprit related to insulin resistance or

inflammation.