ApoL1 levels in high density lipoprotein and cardiovascular event presentation in patients with familial hypercholesterolemia

Abstract

Familial hypercholesterolemia (FH) is one of the most prevalent genetic disorders associated with premature coronary artery disease (CAD) (1). This disorder appears by mutations in the gene that encodes the LDL receptor (LDLR) and it is characterized by a lifelong exposure to high plasma LDL-cholesterol levels (LDL-C). FH patients show an important decrease in their life expectancy because of an increase in CAD frequency, the principal causes of mortality being sudden death and myocardial infarction (2). Clinical expression of CAD in FH patients varies considerably across cohorts and individual patients treated to guidelines (3, 4), suggesting the contribution of additional factors to the atherosclerotic burden in these patients. Indeed, a recent study has reported lipoprotein (a) [Lp(a)] levels as one of those additional factors that influence CVD in FH patients (5).HDLs have proved to be atheroprotective in several epidemiological, clinical, and experimental studies (6-13). Indeed, HDLs are considered key players in the progression of CAD because of their multiple antiatherogenic effects (14) in addition to their role in reverse cholesterol transport. Increasing evidence suggests that HDL atheroprotective effects lie in HDL composition, highlighting the importance of HDL quality rather that HDL quantity in CVD (14-17). Moreover, the existence of several HDL subpopulations with differential contribution to these HDL-related antiatherogenic properties has underscored the relevance of HDL composition in HDL functionality (15,18).A recent study has demonstrated that FH is associated with quantitative and qualitative modifications of HDL Abstract HDL composition rather than HDL-cholesterol (HDL-C) levels seems to be a key determinant of HDL-induced atheroprotection. Heterozygous familial hypercholesterolemia (FH) patients, with lifelong exposure to high LDL levels, show a high prevalence of premature coronary artery disease. We hypothesized that HDL of FH patients might have a modified protein composition and investigated the proteomic signature of HDL obtained from FH patients and their unaffected relatives. HDLs were characterized by 2D electrophoresis/MS in 10 families from the SAFE-HEART cohort (3 individuals/family: 2 with genetic FH diagnosis and 1 non-FH relative) clinically characterized and treated as per guidelines. FH patients had lower apoA-I levels and a differential HDL distribution profile of apoL1 and apoA-IV. ELISA validation revealed decreased apoL1 serum levels in FH patients. ApoL1 levels were able to predict presentation of an ischemic cardiac event, and apoL1/HDL-C ratio was associated with the survival rate after the event. FH patients who died because of a fatal cardiac event had lower apoL1 and LCAT content in HDL3 an average of 3.5 years before the event than those who survived. Changes in HDL protein composition could affect patients' prognosis. The proteomic profile of apoL1 is modified in HDLs of high cardiovascular risk patients, and apoL1 plasma levels are significantly lower in serum...

High density lipoproteins and kidney function: the friend turned foe?

“…Indeed, we have recently demonstrated in an experimental preclinical model that HDL from hypercholesterolemic pigs are less protective than those of normocholesterolemic animals against cardiac ischemia/reperfusion injury (12). Additionally, we have found important changes in the HDL proteomic distribution in familial hypercholesterolemia patients that seem to predispose to cardiovascular event presentation and mortality (10).…”

“…Indeed, CKD has been associated with a diminished lecithin-cholesterol acyltransferase (LCAT) gene expression by the liver reducing its circulating levels and activity (20)(21)(22) and directly impacting HDL maturation. Interestingly, LCAT changes, specifically in the HDL3 subfraction, have been found in high risk patients previous to the presentation of a fatal ischemic event (10). In this context, a loss of HDL protective properties could be behind the elevated risk for cardiovascular events and mortality in patients with kidney disease.…”

“…This discrepancy between HDL-C levels and HDL functionality becomes even more important in the presence of high cardiovascular risk situations such as hypercholesterolemia, diabetes or renal disease in which shifts in HDL lipidic and proteomic distribution could directly affect HDL functionality disrupting the association between HDL-C levels and protection (10,11). Indeed, we have recently demonstrated in an experimental preclinical model that HDL from hypercholesterolemic pigs are less protective than those of normocholesterolemic animals against cardiac ischemia/reperfusion injury (12).…”

Lipoproteomics Environmental and Genetic Factors Affecting High-Density Lipoprotein (HDL)

“…The protein is also believed to exert an as yet undefined function in HDL since low levels predict the risk of CVD. Furthermore, genetic variants of apoL-1 increase the risk of CVD [Cubedo et al 2016, Ito et al 2014. ApoM is a member of the lipocalin family and forms a barrel structure with a small hydrophobic binding pocket that has the capacity of binding small lipids.…”

“…It is possible that some of the proteomic changes observed, including increased apoL-1 in HDL or free apoE, may affect cholesterol efflux or anti-oxidative function. As such, apoL-1 is mainly expressed in the more anti-oxidative HDL3 fraction, and low levels of apoL-1 have recently been proposed as a predictor for future CVD [Cubedo et al 2016]. However, the effect of apoL-1 and its glycosylation in anti-oxidative and cholesterol efflux mechanisms remains to be determined.…”