br Transparency document br Introduction
Introduction High density lipoprotein (HDL) is a macromolecular assembly of proteins and lipids circulating in blood. In recent decades it has attracted the attention of the biomedical CFTRinh-172 mainly due to the inverse relationship between blood HDL-cholesterol (HDL-C) levels with the risk of developing atherosclerosis and coronary heart disease (CHD) [, , , , , , ]. However, the failure of a number of HDL-C raising drugs to reduce CHD morbidity and mortality [4,5] led to the conclusion that simply increasing plasma HDL-C levels only may not be an effective strategy for the prevention and treatment of CHD [4,7]. Moreover, it reinforced the principle that HDL particle functionality may be more important in atheroprotection than HDL-C levels alone [4,7]. HDL particles may be discoidal or spherical with varying diameters . Their biogenesis involves lipid transporters ATP-binding cassette A1 and G1 (ABCA1 and ABCG1, respectively) which are responsible for cholesterol efflux, and the plasma enzyme Lecithin:Cholesterol Acyl Transferase (LCAT), which catalyzes the esterification of free cholesterol and converts HDL from discoidal to spherical particles. In addition, cholesteryl-ester transfer protein (CETP) and phospholipid transfer protein (PLTP) further process HDL in plasma, resulting in spherical particles of different diameters [, , , , ]. Studies in mouse models showed that in addition to apolipoprotein A1 (APOA1) other apolipoproteins, such as APOE  and APOC3  may also promote de novo biogenesis of HDL, independently of pre-existing classical APOA1-containing HDL . APOE- and APOC3-containing HDL particles appear structurally and functionally distinct from APOA1-containing HDL and from each other [16,17]. Notably, the apolipoprotein composition of HDL is a decisive factor for its lipid cargo and overall functionality [, , , ]. In agreement with data from animal studies, studies in humans indicate that variations in apolipoprotein content of HDL set the basis for its functional heterogeneity among individuals , and that differences in lipid composition may result in HDL of either discoidal or spherical shapes [4,7]. Specifically, reduced levels of APOA1 and concomitant elevated content of APOC3 and APOE in HDL correlate with less functional HDL [18,19]. Adipose tissue consists of white adipose tissue (WAT) and brown adipose tissue (BAT): the former is mainly responsible for lipid storage, and the latter for energy production (heat and ATP). Under certain circumstances WAT may be activated metabolically and turn into BRITE (BRown Into whiTE) adipose tissue that can produce heat via non-shivering thermogenesis . The latter phenomenon results from an elevated mitochondrial metabolic activity, mainly of uncoupling protein 1 (Ucp1) function, which mediates the metabolic conversion of free fatty acids to heat, thus contributing to the lean phenotype [22,23]. However, induction of WAT mitochondrial oxidative phosphorylation for ATP production, independently of Ucp1 increase, may also contribute to the lean phenotype . Metabolic activation of WAT into BRITE is considered a promising strategy for treatment of morbid obesity and numerous experimental drugs have been designed towards this goal, though to this date the molecular targets for such interventions remain vague. It is generally agreed that dysfunctional adipose organ predisposes to type 2 diabetes mellitus (T2DM) and other pathological components of the metabolic syndrome . T2DM is a major global health problem, affecting over 300 million people worldwide . It develops because of reduced glucose tolerance, initially manifested as peripheral resistance, and consequently impaired insulin production and secretion by pancreatic β-cells. Recently, considerable attention has been put on the role of HDL in the regulation of β-cell secretory function and peripheral insulin sensitivity. Indeed, data from numerous studies strongly support the hypothesis that pancreatic β-cells, as well as skeletal muscles and adipose tissues could benefit from improved HDL functionality . Yet, although many studies explored the correlation between HDL-C levels and the risk of developing T2DM [, , ], the effects of HDL structure on the disease remain poorly investigated.