Biological Consequences of Dysfunctional HDL

Abstract

Epidemiological studies have suggested an inverse correlation between high density lipoprotein (HDL) cholesterol levels and the risk of cardiovascular disease. HDLs promote reverse cholesterol transport (RCT) and possess several putative atheroprotective functions, associated to the anti-inflammatory, anti-thrombotic and anti-oxidant properties as well as to the ability to support endothelial physiology. The assumption that increasing HDL-C levels would be beneficial on cardiovascular disease (CVD), however, has been questioned as, in most clinical trials, HDL-C-raising therapies did not result in improved cardiovascular outcomes. These findings, together with the observations from Mendelian randomization studies showing that polymorphisms mainly or solely associated with increased HDL-C levels did not decrease the risk of myocardial infarction, shift the focus from HDL-C levels toward HDL functional properties. Indeed, HDL from atherosclerotic patients not only exhibit impaired atheroprotective functions but also acquire pro-atherogenic properties and are referred to as "dysfunctional" HDL; this occurs even in the presence of normal or elevated HDL-C levels. Pharmacological approaches aimed at restoring HDL functions may therefore impact more significantly on CVD outcome than drugs used so far to increase HDL-C levels. Aims of this review is to discuss the pathological conditions leading to the formation of dysfunctional HDL and their role in atherosclerosis and beyond.

Circulating HDL levels control hypothalamic astrogliosis via apoA-I

“…Collectively, all these data indicate that HDL cholesterol concentration in the blood is only giving a static snapshot of a very dynamic and heterogeneous metabolic milieu and is thus unlikely itself causally protective against CVD. It seems more plausible that HDL function is a better predictor of CVD compared with its simple level in the blood, as has been repeatedly shown by several independent groups (40,41) In conclusion, our results point to a novel role of HDLs in maintaining normal hypothalamic function. Circulating HDLs and their major protein component, apoA-I, have several beneficial functions for brain cell metabolism, including effects on endothelial repair, inflammation, A metabolism, and cognitive function, and all of these suggest an HDL-based therapy as a potential treatment for metabolic disease.…”

Arylesterase Activity of HDL Associated Paraoxonase as a Potential Prognostic Marker in Patients With Sepsis and Septic Shock—A Prospective Pilot Study

“…ICU mortality and 28-day mortality were 36 and 47%, respectively ( Table 1). Non-sepsis control patients received catecholamine therapy on median 1 (0-2) day, and median ICU and hospital length of stay were 3 (2-6) and 15 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) days, respectively. As expected, inflammatory markers including white blood count (WBC; 14.9 vs. 9.1 g/L, p = 0.011), CRP (213 vs. 12 mg/l, p < 0.0001; normal range <5 mg/l), and PCT (8.8 vs. 0.15 ng/ml, p < 0.0001) were higher in sepsis patients compared to ICU controls.…”

“…HDL also have antioxidative properties, can activate the endothelial nitric oxide synthase (eNOS), and reduce adhesion molecule expression in vascular endothelial cells (6,8,(10)(11)(12). Antioxidative mechanisms are altered in dysfunctional HDL, which has been identified in several chronic diseases including end stage renal disease, psoriasis, rheumatoid arthritis, and diabetes (13)(14)(15). Qualitative changes of HDL such as cholesterol efflux capacity (CEC) and the antioxidative and anti-inflammatory arylesterase activity of HDL-associated paraoxonase (AEA) have, to date, sparsely been investigated in septic patients (16)(17)(18).…”

Lipoprotein profiling in early multiple sclerosis patients: effect of chronic inflammation?

“…HDL-C possesses atheroprotective functions and anti-inflammatory properties, but with the onset of systemic inflammation, it may become pro-inflammatory [33]. The dysfunctional HDL-C particles are those, which lost their atheroprotective features and can even exhibit the pro-atherogenic ones [38]. The causes of this phenomenon can be explained by amyloidosis and other translational and posttranslational modifications of apolipoprotein A-1 (apoA-1) [34].…”