Abstract
For a long time, high-density lipoprotein cholesterol (HDL-C) has been regarded as a cardiovascular disease (CVD) protective factor. Recently, several epidemiological studies, while confirming low plasma levels of HDL-C as an established predictive biomarker for atherosclerotic CVD, indicated that not only people at the lowest levels but also those with high HDL-C levels are at increased risk of cardiovascular (CV) mortality. This “U-shaped” association has further fueled the discussion on the pathophysiological role of HDL in CVD. In fact, genetic studies, Mendelian randomization approaches, and clinical trials have challenged the notion of HDL-C levels being causally linked to CVD protection, independent of the cholesterol content in low-density lipoproteins (LDL-C). These findings have prompted a reconsideration of the biological functions of HDL that can be summarized with the word “HDL functionality”, a term that embraces the many reported biological activities beyond the so-called reverse cholesterol transport, to explain this lack of correlation between HDL levels and CVD. All these aspects are summarized and critically discussed in this review, in an attempt to provide a background scenario for the “HDL story”, a lipoprotein still in search of a role.
Highlights
Current knowledge on the relevance of high-density lipoproteins and their cholesterol content (HDL-C) in the initiation and evolution of atherosclerotic cardiovascular diseases (CVDs) has dramatically changed over recent years.In epidemiological studies, low levels of HDL-C are predictive of an increased risk of CVD, and this has led to searching for a role for HDL in modulating pathways involved in atherosclerosis
We briefly summarize recent data from observational, epidemiological, genetic, and Mendelian randomization studies linking HDL to CVD; we analyze the outcomes from trials with HDL-C-increasing strategies (e.g., cholesteryl ester transfer protein (CETP) inhibitors) and trials with reconstituted HDL or apolipoprotein A-I to better understand the role of the “HDL
Similar deductions come from genetics, where the combined exposure to genetic variants mimicking the action of CETP inhibitors and statins was significantly associated with a corresponding reduction in the risk of cardiovascular events that was proportional to the attenuated reduction in apoB, but significantly less than expected per unit change in low-density lipoprotein cholesterol (LDL-C) [50], perhaps due to the lack of return of cholesterol to apoB-containing lipoproteins by the inhibition of CETP
Summary
Current knowledge on the relevance of high-density lipoproteins and their cholesterol content (HDL-C) in the initiation and evolution of atherosclerotic cardiovascular diseases (CVDs) has dramatically changed over recent years. Low levels of HDL-C are predictive of an increased risk of CVD, and this has led to searching for a role for HDL in modulating pathways involved in atherosclerosis. The most popular suggested role has been the socalled reverse cholesterol transport, a metabolic pathway by which HDL can remove cholesterol form lipid-laden cells present in the arterial wall and deliver it to the liver for excretion, at least in part, with the bile. These findings have prompted efforts to discover pharmacological therapies aimed at increasing HDL-C levels. We briefly summarize recent data from observational, epidemiological, genetic, and Mendelian randomization studies linking HDL to CVD; we analyze the outcomes from trials with HDL-C-increasing strategies (e.g., CETP inhibitors) and trials with reconstituted HDL or apolipoprotein A-I to better understand the role of the “HDL story” in CVD, and to propose future pathways of research
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