With a prevalence of 30-50% and clear association with increased cardiovascular disease (CVD), Metabolic Syndrome (MetS) is emerging as a major public health problem. MetS is characterized by elevated markers of inflammation, hypertriglyceridemia, and low levels of high density lipoprotein (HDL). This proposal aims to understand how HDL metabolism and function are altered in MetS. In MetS, increases in triglyceride-rich lipoproteins (TGRL) in combination with increased activity of cholesterol ester transfer protein (CETP) leads to TG enrichment of HDL. Although there is evidence that TG enrichment per se may destabilize the particle to promote release of apoA-I, it is likely that HDL remodeling factors in the circulation act on TG-enriched HDL to amplify apoA-I release and catabolism. Based on our preliminary data, we propose that circulating phospholipases (endothelial lipase, Group IIA secretory phospholipase A2) contribute significantly to HDL remodeling in MetS by liberating lipid-poor apoA-I from TG-enriched HDL. Once released from remodeled HDL, lipid-poor apoA-I has three potential fates: it may serve as an acceptor for cellular cholesterol efflux, associate with circulating HDL, or be cleared from the circulation due to a failure to undergo re-lipidation. Emerging evidence indicates that not all lipid-poor apoA-I species are capable of acquiring additional lipid and are thus susceptible to rapid catabolism. We propose that HDL lowering in MetS is due not only to enhanced HDL remodeling to amplify the release of lipid-poor apoA-I, but is also due to the increased production of """"""""dysfunctional"""""""" lipid-poor species that are inherently susceptible to catabolism. The HDL receptor SR-BI plays a key role in HDL metabolism by mediating the selective uptake of CE from the core of HDL particles into cells. We have shown that SR-BI processing of HDL from healthy subjects generates at least 3 distinct lipid-depleted HDL """"""""remnants"""""""" that differ in composition and subsequent metabolism. We propose that as SR-BI depletes the core of TG-enriched MetS HDL, the propensity of such particles to remodel leads to enhanced released of lipid-poor apoA-I. The central hypothesis of this proposal is that TG enrichment of HDL in MetS predisposes the particle to remodeling by intravascular factors and alters its processing by SR-BI, leading to the generation of lipid-poor species that are susceptible to catabolism. Specific Objective 1: Test the hypothesis that enhanced remodeling of HDL in hypertriglyceridemic MetS subjects leads to generation of lipid-poor apoA-I. The goal is to identify specific features of MetS HDL and/or MetS plasma that predict susceptibility to remodeling. We will also determine whether fibrate-induced TG lowering in MetS subjects leads to altered HDL remodeling. Specific Objective 2: Test the hypothesis that enhanced remodeling of TG-enriched HDL leads to alterations in subsequent HDL metabolism. Specific Objective 3: Test the hypothesis that TG enrichment alters SR-BI metabolism of HDL. Results from this project will provide new insights into mechanisms underlying reduced HDL in MetS, a prevalent condition in the Veteran population that significantly increases the risk of developing CVD. Findings from this project have the potential to define novel biological correlates of accelerated apoA-I catabolism in MetS and to identify MetS subjects most likely to benefit from TG lowering/HDL raising interventions.
The metabolic syndrome (MetS) is a complex disorder that increases the risk for diabetes, heart disease, and stroke. The incidence of MetS has reached epidemic proportions in the United States, including the Veteran population. A common feature of MetS is low HDL cholesterol (HDL-C), which is recognized as a major risk factor for heart disease and stroke. Previous research indicates that HDL in individuals with MetS is more rapidly cleared from the blood compared to people without MetS. This proposal seeks to understand why HDL in MetS subjects is more susceptible to clearance. Results from these studies may identify new strategies for the clinical management of individuals with MetS.