LDL-associated apolipoprotein J and lysozyme are associated with atherogenic properties of LDL found in type 2 diabetes and the metabolic syndrome

Abstract

Objectives. Exchangeable low-density lipoprotein (LDL)-associated proteins can affect the atherogenic properties of LDL. Our aim was to analyse the protein composition of LDL from individuals with or without type 2 diabetes and the metabolic syndrome (T2DM) in relation to other LDL particle characteristics, to assess whether certain proteins associate more with certain subclasses of LDL typical for T2DM, such as small, apoCIII-rich LDL.Design. Low-density lipoprotein from two cohorts of 61-year-old men (n = 19 and 64) with or without T2DM was isolated using size-exclusion chromatography or deuterium oxide-based ultracentrifugation. LDLassociated proteins were identified using mass spectrometry and quantified using two-dimensional gel electrophoresis or enzyme-linked immunosorbent assay. Differently expressed LDL-associated proteins apolipoprotein (apo)J and lysozyme were also measured in serum from a third cohort of women (n = 71) with or without T2DM. Lysozyme binding to advanced glycation end product (AGE)-LDL was examined in vitro.Results. ApoJ and lysozyme were increased in LDL particles with increased apoCIII content and decreased cholesterol content. When isolated with size-exclusion chromatography, LDL from individuals with T2DM contained more apoJ and lysozyme and less apoA1 than LDL from control individuals. LDL content of apoJ correlated with a smaller LDL particle size. Serum levels of lysozyme, but not apoJ, were increased in individuals with T2DM. In vitro, lysozyme associated more with AGE-LDL than with unmodified LDL. Conclusions.Our results indicate that apoJ and lysozyme are increased in LDL with characteristics of small dense LDL in T2DM. Small dense LDL is easily glycated, and the increased affinity of lysozyme for AGE-LDL provides a possible partial explanation for an increase lysozyme in LDL from those with type 2 diabetes.

Increased concentration of clusterin/apolipoprotein J (apoJ) in hyperlipemic serum is paradoxically associated with decreased apoJ content in lipoproteins

“…The content of apoJ in lipoproteins is altered in patients with coronary heart disease or with CVR factors, including obesity, insulin resistance and dyslipidemia [13,14,29,32]. It has been shown that a low content of apoJ in HDL may compromise the anti-apoptotic function of this lipoprotein in patients with coronary heart disease [13].…”

“…HDL proteome remodeling in CAD, in particular increased apoC-III and decreased apoJ content, impairs the activation of endothelial antiapoptotic pathways [13]. Other authors have reported that apoJ content in LDL is increased in diabetic patients [29]. These findings suggest that the distribution of apoJ is abnormal in subjects with high CVR.…”

Clusterin/apolipoprotein J binds to aggregated LDL in human plasma and plays a protective role against LDL aggregation

“…Although all proteomic analyses performed in LDL have detected the presence apoJ in this lipoprotein, few studies have investigated the role of apoJ on LDLs. Karlsson et al reported that apoJ is increased in LDLs from obese subjects (54), and Pettersson et al described increased apoJ content in small dense LDLs from patients with diabetes and metabolic syndrome (20). These findings suggest that the low content of apoJ in HDLs in these patients could be caused by an altered distribution of apoJ among the lipoprotein fractions.…”

“…However, studies on the relationship between apoJ and very LDLs or LDLs are scarce, and the role of apoJ in these lipoproteins is virtually unknown. Petterson et al described that, in diabetic patients, the content of apoJ is increased in small dense LDLs (20), an atherogenic form of LDLs related with high CVR. Schwarz et al reported that apoJ binds to LDLs treated with cholesteryl esterase and plasmin [enzymatically modified LDLs (E-LDLs)] (21), inhibiting its cytotoxic capacity.…”

Clusterin: full-length protein and one of its chains show opposing effects on cellular lipid accumulation

“…Indeed, commonly known polymorphisms in clusterin gene are positively correlated with the risk of type-II diabetes (T2DM)22. However, there are unclear reports on the correlation between serum clusterin concentration and T2DM232425. Similarly, unclear reports also exist for correlation between levels of clusterin and obesity2526.…”