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High-density lipoproteins (HDLs) exert many beneficial effects which may help to protect against the development or progression of atherosclerosis or even facilitate lesion regression. These activities include promoting cellular cholesterol efflux, protecting low-density lipoproteins (LDLs) from modification, preserving endothelial function, as well as anti-inflammatory and antithrombotic effects. However, questions remain about the relative importance of these activities for atheroprotection. Furthermore, the many molecules (both lipids and proteins) associated with HDLs exert both distinct and overlapping activities, which may be compromised by inflammatory conditions, resulting in either loss of function or even gain of dysfunction. This complexity of HDL functionality has so far precluded elucidation of distinct structure–function relationships for HDL or its components. A better understanding of HDL metabolism and structure–function relationships is therefore crucial to exploit HDLs and its associated components and cellular pathways as potential targets for anti-atherosclerotic therapies and diagnostic markers.

The prevalence of type 2 diabetes mellitus and of the metabolic syndrome is rising worldwide and reaching epidemic proportions. These pathologies are associated with significant morbidity and mortality, in particular with an excess of cardiovascular deaths. Type 2 diabetes mellitus and the cluster of pathologies including insulin resistance, central obesity, high blood pressure, and hypertriglyceridemia that constitute the metabolic syndrome are associated with low levels of HDL cholesterol and the presence of dysfunctional HDLs. We here review the epidemiological evidence and the potential underlying mechanisms of this association. We first discuss the well-established association of type 2 diabetes mellitus and insulin resistance with alterations of lipid metabolism and how these alterations may lead to low levels of HDL cholesterol and the occurrence of dysfunctional HDLs. We then present and discuss the evidence showing that HDL modulates insulin sensitivity, insulin-independent glucose uptake, insulin secretion, and beta cell survival. A dysfunction in these actions could play a direct role in the pathogenesis of type 2 diabetes mellitus.

High-density lipoprotein (HDL) has attracted interest as a therapeutic target in cardiovascular diseases in recent years. Although many functional mechanisms of the vascular protective effects of HDL have been identified, increasing the HDL plasma level has not been successful in all patient cohorts with increased cardiovascular risk. The composition of the HDL particle is very complex and includes diverse lipids and proteins that can be modified in disease conditions. In patients with chronic kidney disease (CKD), the accumulation of uremic toxins, high oxidative stress, and chronic micro-inflammatory conditions contribute to changes in the HDL composition and may also account for protein/lipid modifications. These conditions are associated with a decreased protective function of HDL. Therefore, the HDL quantity and the functional quality of the particle must be considered.

This review summarizes the current knowledge of dyslipidemia in CKD patients, the effects of lipid-modulating therapy, and the structural modifications of HDL that are associated with dysfunction.

The cholesterol of high-density lipoproteins (HDLs) and its major proteic component, apoA-I, have been widely investigated as potential predictors of acute cardiovascular (CV) events. In particular, HDL cholesterol levels were shown to be inversely and independently associated with the risk of acute CV diseases in different patient populations, including autoimmune and chronic inflammatory disorders. Some relevant and direct anti-inflammatory activities of HDL have been also recently identified targeting both immune and vascular cell subsets. These studies recently highlighted the improvement of HDL function (instead of circulating levels) as a promising treatment strategy to reduce inflammation and associated CV risk in several diseases, such as systemic lupus erythematosus and rheumatoid arthritis. In these diseases, anti-inflammatory treatments targeting HDL function might improve both disease activity and CV risk. In this narrative review, we will focus on the pathophysiological relevance of HDL and apoA-I levels/functions in different acute and chronic inflammatory pathophysiological conditions.

During infection significant alterations in lipid metabolism and lipoprotein composition occur. Triglyceride and VLDL cholesterol levels increase, while reduced HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) levels are observed. More importantly, endotoxemia modulates HDL composition and size: phospholipids are reduced as well as apolipoprotein (apo) A-I, while serum amyloid A (SAA) and secretory phospholipase A2 (sPLA2) dramatically increase, and, although the total HDL particle number does not change, a significant decrease in the number of small- and medium-size particles is observed. Low HDL-C levels inversely correlate with the severity of septic disease and associate with an exaggerated systemic inflammatory response. HDL, as well as other plasma lipoproteins, can bind and neutralize Gram-negative bacterial lipopolysaccharide (LPS) and Gram-positive bacterial lipoteichoic acid (LTA), thus favoring the clearance of these products. HDLs are emerging also as a relevant player during parasitic infections, and a specific component of HDL, namely, apoL-1, confers innate immunity against trypanosome by favoring lysosomal swelling which kills the parasite. During virus infections, proteins associated with the modulation of cholesterol bioavailability in the lipid rafts such as ABCA1 and SR-BI have been shown to favor virus entry into the cells. Pharmacological studies support the benefit of recombinant HDL or apoA-I mimetics during bacterial infection, while apoL-1–nanobody complexes were tested for trypanosome infection. Finally, SR-BI antagonism represents a novel and forefront approach interfering with hepatitis C virus entry which is currently tested in clinical studies. From the coming years, we have to expect new and compelling observations further linking HDL to innate immunity and infections.

Besides their well-documented function of reverse transport of cholesterol, high-density lipoproteins (HDLs) display pleiotropic effects due to their antioxidant, antithrombotic, anti-inflammatory and antiapoptotic properties that may play a major protective role in acute stroke, in particular by limiting the deleterious effects of ischaemia on the blood–brain barrier (BBB) and on the parenchymal cerebral compartment. HDLs may also modulate leukocyte and platelet activation, which may also represent an important target that would justify the use of HDL-based therapy in acute stroke. In this review, we will present an update of all the recent findings in HDL biology that could support a potential clinical use of HDL therapy in ischaemic stroke.

Epidemiological studies support a strong association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. Experimental evidence from different angles supports the view that low HDL is unlikely an innocent bystander in the development of heart failure. HDL exerts direct cardioprotective effects, which are mediated via its interactions with the myocardium and more specifically with cardiomyocytes. HDL may improve cardiac function in several ways. Firstly, HDL may protect the heart against ischaemia/reperfusion injury resulting in a reduction of infarct size and thus in myocardial salvage. Secondly, HDL can improve cardiac function in the absence of ischaemic heart disease as illustrated by beneficial effects conferred by these lipoproteins in diabetic cardiomyopathy. Thirdly, HDL may improve cardiac function by reducing infarct expansion and by attenuating ventricular remodelling post-myocardial infarction. These different mechanisms are substantiated by in vitro, ex vivo, and in vivo intervention studies that applied treatment with native HDL, treatment with reconstituted HDL, or human gene transfer. The effect of human gene transfer on infarct expansion and ventricular remodelling post-myocardial infarction illustrates the beneficial effects of HDL on tissue repair. The role of HDL in tissue repair is further underpinned by the potent effects of these lipoproteins on endothelial progenitor cell number, function, and incorporation, which may in particular be relevant under conditions of high endothelial cell turnover. Furthermore, topical HDL therapy enhances cutaneous wound healing in different models. In conclusion, the development of HDL-targeted interventions in these strategically chosen therapeutic areas is supported by a strong clinical rationale and significant preclinical data.

The main lifestyle interventions to modify serum HDL cholesterol include physical exercise, weight loss with either caloric restriction or specific dietary approaches, and smoking cessation. Moderate alcohol consumption can be permitted in some cases. However, as these interventions exert multiple effects, it is often difficult to discern which is responsible for improvement in HDL outcomes. It is particularly noteworthy that recent data questions the use of HDL cholesterol as a risk factor and therapeutic target since randomised interventions and Mendelian randomisation studies failed to provide evidence for such an approach. Therefore, these current data should be considered when reading and interpreting this review. Further studies are needed to document the effect of lifestyle changes on HDL structure–function and health.

The knowledge of an inverse relationship between plasma high-density lipoprotein cholesterol (HDL-C) concentrations and rates of cardiovascular disease has led to the concept that increasing plasma HDL-C levels would be protective against cardiovascular events. Therapeutic interventions presently available to correct the plasma lipid profile have not been designed to specifically act on HDL, but have modest to moderate effects on plasma HDL-C concentrations. Statins, the first-line lipid-lowering drug therapy in primary and secondary cardiovascular prevention, have quite modest effects on plasma HDL-C concentrations (2–10 %). Fibrates, primarily used to reduce plasma triglyceride levels, also moderately increase HDL-C levels (5–15 %). Niacin is the most potent available drug in increasing HDL-C levels (up to 30 %), but its use is limited by side effects, especially flushing.

The present chapter reviews the effects of established hypolipidemic drugs (statins, fibrates, and niacin) on plasma HDL-C levels and HDL subclass distribution, and on HDL functions, including cholesterol efflux capacity, endothelial protection, and antioxidant properties.

Dyslipidaemia is a major risk factor for cardiovascular diseases. Pharmacological lowering of LDL-C levels using statins reduces cardiovascular risk. However, a substantial residual risk persists especially in patients with type 2 diabetes mellitus. Because of the inverse association observed in epidemiological studies of HDL-C with the risk for cardiovascular diseases, novel therapeutic strategies to raise HDL-C levels or improve HDL functionality are developed as complementary therapy for cardiovascular diseases. However, until now most therapies targeting HDL-C levels failed in clinical trials because of side effects or absence of clinical benefits. This chapter will highlight the emerging small molecules currently developed and tested in clinical trials to pharmacologically modulate HDL-C and functionality including new CETP inhibitors (anacetrapib, evacetrapib), novel PPAR agonists (K-877, CER-002, DSP-8658, INT131 and GFT505), LXR agonists (ATI-111, LXR-623, XL-652) and RVX-208.