Analysis of the Plasma and HDL Lipidomes in Metabolic Syndrome Patients Following Weight Loss and Weight Loss Plus Exercise Treatments

Abstract

Metabolic syndrome (MetS) increases the risk of type 2-diabetes (T2D) and cardiovascular disease (CVD) due in part to altered lipid metabolism and homeostasis. Such metabolic diseases are commonly associated with lower high-density lipoprotein-cholesterol (HDL-C) and decreased functionality, which are considered as independent risk factors for CVD. The lipid composition of HDL may contribute to the HDL functional deficiency in metabolic disease patients. Weight loss and exercise are recommended as a first-line treatment to delay the onset or prevent the progression of T2D and CVD and their associated complications. This may represent a promising approach to normalise lipid metabolism and thereby HDL lipid composition and ultimately enhance HDL function. In this study, we have used a lipidomic approach to characterise the differences in the plasma and HDL lipidomes between MetS patients and healthy individuals. We have combined this with HDL particle size, cholesterol efflux capacity (CEC) and cholesteryl ester transfer protein (CETP) measurements to define the relationships between the HDL lipidome, particle size and CEC. We have also assessed the effect of dietary weight loss (WL) and dietary weight loss plus exercise (WLEX) treatments on the structure composition and function of HDL particles. MetS patients (N=95) were recruited; subsets underwent 12-weeks of no treatment (n=17), WL (n=19), or (WLEX (n=17). A set of plasma samples from age and sex matched healthy individuals were also included. HDL was isolated using density-gradient ultracentrifugation. The plasma and HDL lipidomes (333 species) were analysed by mass spectrometry and the HDL particle size profile was determined by nuclear magnetic resonance. Cholesteryl ester transfer protein (CETP) activity and ex vivo HDL-cholesterol efflux capacity (CEC) were assessed. Compared to the healthy individuals, the MetS patients showed similar plasma and HDL lipid abnormalities to those that have been observed previously in T2D and CVD, particularly in sphingolipids, ether-phospholipids, and di- and triacylglycerol. In MetS patients, the HDL particle profile was shifted toward a smaller particle size, and CEC was lower compared with the healthy individuals. Several HDL lipid classes and species were associated with HDL diameter and CEC. Importantly, we observed normalisation effects toward the healthy individuals in plasma and HDL lipid species, including dihydroceramide, ceramide, lysoalkylphosphatidylcholine, cholesterol ester and di- and triacylglycerols, following WL and WLEX, with greater effects being observed in the WLEX group. Similarly, HDL particle profile showed increased particle size after the WL and WLEX treatments, with greater effects being observed in the latter group. CETP activity was also reduced after the WL and WLEX interventions, and CEC was improved significantly only after WLEX. The plasma and HDL lipidomes are significantly altered in MetS, leading to a higher risk of insulin resistance, T2D and CVD. Dietary modifications and exercise treatment in MetS patients attenuate several important abnormalities in the plasma and HDL lipidomes and HDL particle size profile and ultimately enhance HDL function. HDL lipids associated with reduced particle size and diminished CEC may represent novel biomarkers for the early prediction of HDL dysfunction and potential therapeutic targets for future HDL modifying therapies.