CLINICAL STUDY Fibroblast cholesterol efflux to plasma from metabolic syndrome subjects is not defective despite low high-density lipoprotein cholesterol Robin P F Dullaart 1 , Albert K Groen 2 , Geesje M Dallinga-Thie 3 , Rindert de Vries 1 , Wim J Sluiter 1 and Arie van Tol 1,4 1 Department of Endocrinology, University of Groningen and University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands, Departments of 2 Laboratory of Biochemistry, 3 Laboratory of Experimental Vascular Medicine, Academic Medical Center Amsterdam, The Netherlands and 4 Departments of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands (Correspondence should be addressed to R P F Dullaart; Email: r.p.f.dullaart@int.umcg.nl) Abstract Objective: We tested whether in metabolic syndrome (MetS) subjects the ability of plasma to stimulate cellular cholesterol efflux, an early step in the anti-atherogenic reverse cholesterol transport pathway, is maintained despite low high-density lipoprotein (HDL) cholesterol. Design: In 76 subjects with and 94 subjects without MetS based on the National Cholesterol Education Program Adult Treatment Panel III (NCEPATP III) criteria, we determined plasma (apo)lipoproteins, pre-b-HDL formation, phospholipid transfer protein (PLTP) activity, cholesterol esterification (EST), cholesteryl ester transfer (CET), adiponectin, and the ability of plasma from each subject to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single donor. Results: Apo E, PLTPactivity, EST, and CET were higher (PZ0.04 to !0.001), whereas adiponectin was lower in MetS subjects (P!0.01). Pre-b-HDL and pre-b-HDL formation were not different between subjects with and without MetS. Cellular cholesterol efflux to plasma from MetS subjects was slightly higher versus plasma from subjects without MetS (8.8G1.0 vs 8.5G0.9%, PZ0.05), but the difference was not significant after age, sex, and diabetes adjustment. Cellular cholesterol efflux was positively related to pre-b-HDL formation, EST, PLTPactivity, and apo E (P!0.05 for all by multiple linear regression analysis), without an independent association with MetS and diabetes status. Conclusions: The ability of plasma from MetS subjects to promote fibroblast cholesterol efflux is not defective, although HDL cholesterol is decreased. Higher cholesterol esterification, PLTP activity, and apo E levels may contribute to the maintenance of cholesterol efflux in MetS. European Journal of Endocrinology 158 53–60 Introduction The metabolic syndrome (MetS) represents a cluster of cardiovascular risk factors, including (central) obesity, high blood pressure, high plasma triglycerides, low high- density lipoprotein (HDL) cholesterol, and hyperglycemia (1). In recent years, several expert groups have proposed (and revised) their criteria for MetS (2–5) with the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) criteria, originally appeared in 2001 (3) and being widely used in the literature. The existence of such a syndrome has been criticized, and it has been disputed whether resistance to insulin-stimulated glucose uptake should be regarded as the unifying pathophysiological abnormality (1). None- theless, a systemic review has shown that cardiovascular risk is increased by 65% in subjects fulfilling the NCEPATP III criteria for MetS (6), an observation that was recently extended by the DECODE study group (7). The reverse cholesterol transport (RCT) process directs cholesterol via HDL from the peripheral tissues to the liver for subsequent excretion in the bile, and is considered to represent a pathway that protects against atherosclerosis development (8–10). Efflux of cholesterol from peripheral cells to extracellular acceptors is an important early step in RCT (11, 12). Cellular cholesterol removal is governed by several still incompletely understood mechanisms, includ- ing aqueous diffusion, transport of cholesterol via the ATP-binding cassette (ABC) transporters, ABCA1, and ABCG1, as well as via scavenger receptor class B type 1 (SR-BI) (11–14). Small, lipid-poor, or lipid-free apo A-I- containing particles, commonly designated pre-b-HDL, are considered to be the initial acceptors of cell-derived cholesterol via the ABCA1 transporter (8, 10, 15, 16). Among other factors, the metabolism of these particles is governed in a complex way by phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP), which contribute to pre-b-HDL generation, and by lecithin:cholesterol acyltransferase (LCAT), which European Journal of Endocrinology (2008) 158 53–60 ISSN 0804-4643 q 2008 Society of the European Journal of Endocrinology DOI: 10.1530/EJE-07-0451 Online version via www.eje-online.org