Antioxidative Activity of HDL Particle Subspecies Is Impaired in Hyperalphalipoproteinemia: Relevance of Enzymatic and Physicochemical Properties

Abstract

Objective-Hyperalphalipoproteinemia (HALP) is characterized by elevated plasma levels of high-density lipoprotein (HDL) particles with altered composition, metabolism, and function. The impact of such modification on antioxidative activities of HDL subfractions is indeterminate. Methods and Results-Gradient fractionation revealed that buoyant HDL2b and 2a and small dense HDL3b and 3c levels were elevated up to 2.0-fold in HALP subjects (nϭ9; mean plasma HDL cholesterol, 79 mg/dL) with low hepatic lipase activity. HDL2a, 3a, 3b, and 3c displayed lower specific antioxidative activity (sAA) during low-density lipoprotein (LDL) oxidation (Ϫ15% to Ϫ86%, on a unit particle mass basis) than their normolipidemic counterparts (nϭ13). LDL oxidation was delayed by control HDL3a, 3b, and 3c (up to Ϫ79%) but specifically by HDL3c (Ϫ54%) in HALP. Paraoxonase activity was deficient in all HALP HDL subfractions. Paraoxonase, PAF-AH, and LCAT activities together accounted for Ϸ50% of variation in sAA. Abnormal chemical composition of HDL3b and 3c (cholesterol-deficient, triglyceride-enriched) in HALP was associated with impaired sAA. Systemic oxidative stress (as plasma 8-isoprostanes) tended to be elevated (1.5-fold) in HALP and negatively correlated with sAA (as TBARS). Conclusions-Intrinsic

High-density lipoprotein subfractions display proatherogenic properties in overweight and obese children

“…In adults, this association renders HDL proatherogenic, with a loss or reduction of many of its functions, including its reverse cholesterol transport and antioxidant properties (15,(28)(29)(30). Therefore, we suggest that this would also be the case in SAA-enriched HDL from overweight and obese children; in support of this concept, we have shown that the activities of HDL 2 -CETP and HDL 2 -LCAT were also influenced in these overweight and obese cohorts.…”

Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis

“…In this study, plasma TG levels were markedly elevated (ϩ76%) in CHD patients compared with control subjects (Ansell et al, 2003), suggesting that concomitant HDL enrichment in TG might have significantly contributed to the formation of dysfunctional HDL as proposed elsewhere (Hansel et al, 2004;Kontush et al, 2004Kontush et al, , 2005Nobecourt et al, 2005).…”

“…The specific association of the deficient antioxidative activity with small, dense HDL (Hansel et al, 2004;Kontush et al, 2004Kontush et al, , 2005Nobecourt et al, 2005) together with the direct mechanistic link between antiinflammatory and antioxidative activities (Navab et al, 2001a,b) suggests that small, dense HDL is a major subset of the total HDL particle population, which is responsible for both potent anti-inflammatory activity under normal conditions and for deficient activity under pro-atherogenic, pro-inflammatory conditions. This conclusion is consistent with the corrected anti-inflammatory properties of HDL from PLTP-deficient mice, which are characterized by the prevalence of small, lipid-poor HDL particles (Yan et al, 2004).…”

Effect of open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA

“…The increase in the unesterifi ed cholesterol content and subsequent increase in esterifi ed cholesterol content within the HDL fraction following CER-001 infusion indicates that the apoA-I within the CER-001 particle is recognized by endogenous LCAT, responsible for cholesterol esterifi cation in plasma ( 27 ). However, the increased HDL-c following CER-001 infusion consisted predominantly of unesterifi ed cholesterol, whereas normally the HDL fraction of cholesterol contains more esterifi ed than unesterifi ed cholesterol ( 28 ). These fi ndings imply suboptimal esterifi cation of the cholesterol mobilized by CER-001.…”