HDL Lipoproteins

The entrapment of LDLs by proteoglycans (PGs) in the extracellular matrix of the arterial intima is a key initial step in the development of atherosclerosis. HDLs can interfere with this process, but the underlying mechanism is not fully understood. The aim of this study was to investigate the mechanisms by which HDL inhibits LDL binding to PG. An In-Cell ELISA was used to measure the binding of LDL to PGs in the extracellular matrix synthesized by mouse vascular smooth muscle cells. Fast-protein liquid chromatography, immunoprecipitation, SDS-PAGE, and immunoblotting analysis were performed to characterize how HDL and its apolipoproteins inhibit LDL binding to PGs. HDL and APOA1 inhibited LDL binding to PGs in a dose-dependent manner. Competition experiments showed that HDL did not compete directly with LDL for PG binding. Instead, APOA1 dissociated from HDL and associated with LDL, reducing the ability of LDL to bind PGs. This was demonstrated by separating HDL and LDL using porous filters of different sizes and tracking the movement of either HDL or APOA1. When APOA1 was solidly anchored to HDL particles, HDL lost the ability to affect LDL-PG binding. HDL inhibits LDL binding to PGs through an interaction with its main apolipoprotein, APOA1, specifically, a pool of loosely attached, exchangeable, lipid-free APOA1 on the HDL surface. These findings identify lipid-free APOA1 as a critical mediator of the ability of HDL to reduce LDL retention in the arterial wall and provide new insights into the antiatherogenic properties of HDL.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial hepatic manifestation of metabolic syndrome, such as aberrant lipid accumulation. Celastrol (CEL), a potent leptin sensitizer, has been studied for the treatment of MASLD; however, its clinical application is hindered by its low oral bioavailabilities and high toxicities. Herein, CEL is encapsulated into the micelles of poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate]-block-poly(ε-caprolactone) (OPDEA-PCL), whose shell is capable of fast penetrating mucus due to its protein-non-fouling and rapid transcytosis induction as a result of phospholipid-binding characteristic. After oral administration, OPDEA-PCL/CEL micelles sequentially permeated through the gastrointestinal barriers into the blood. Notably, it is found that OPDEA-PCL/CEL specifically captured high-density lipoproteins (HDL) in plasma, forming an HDL corona actively targeting the hepatocytes, delivering a high concentration of CEL. In the MASLD mouse model, oral administration of OPDEA-PCL/CEL effectively alleviated hepatic lipid accumulation, lessened hepatic inflammation, and mitigated the toxicities of CEL with therapeutic efficacy superior to free CEL and PEG-PCL/CEL and even the current clinical simvastatin. Therefore, the OPDEA-PCL may be a promising oral CEL delivery system for treating MASLD.

BackgroundThe cholesterol, high-density lipoprotein, and glucose (CHG) index has emerged as a novel biomarker for insulin resistance (IR) and metabolic syndrome (MS). However, its prognostic role in IgA nephropathy (IgAN) remains underexplored. This study investigated the association between the CHG index and IgAN and aimed to clarify the importance of the CHG index in evaluating the prognosis of IgAN.MethodsThis single-centre retrospective study included 1791 patients with biopsy-confirmed IgAN who had more than 12 months of follow-up from October 2014 to September 2023. The optimal CHG index cut-off for renal endpoints was determined using receiver operating characteristic (ROC) analysis. Associations were assessed via correlation analysis, Cox regression, and Kaplan-Meier survival analysis.ResultsPatients were stratified into three baseline CHG index tertiles. High baseline CHG index was correlated with adverse clinicopathological features and reduced renal survival (Kaplan-Meier, log-rank=26.51; P5.29; n=695). Subgroup analysis revealed that elevated CHG indices had a more pronounced prognostic value for renal outcomes in subgroups of patients with a BMI ≤ 24.9, a 24-hour urine protein level ≤ 3.5 g, an estimated glomerular filtration rate (eGFR)≤45 mL/min/1.73m², and an Oxford renal pathology classification (MEST-C)T0. Multivariate Cox regression analysis demonstrated that elevated CHG indices were significantly associated with worse renal outcomes in patients with IgAN (adjusted HR: 1.842; 95% CI: 1.044-3.249; P = 0.035).ConclusionElevated CHG index is an independent risk factor for predicting renal prognosis in IgAN. Compared with patients with low CHG indices, those with CHG indices > 5.29 have an 84.2% greater risk of poor renal outcomes.

AimsLow plasma high-density lipoprotein (HDL)-cholesterol levels are associated with increased risk of atherosclerotic cardiovascular disease (ASCVD), potentially reflecting impaired antiatherogenic HDL functions. These latter are strongly influenced by the HDL phospholipidome, which is frequently altered in ASCVD patients. Several studies reported that plasma levels of phosphatidylethanolamine (PE) species, particularly PE (36:5), were positively associated with ASCVD, but the underlying mechanisms remain unclear. Plasma PE (36:5) exists as eicosapentaenoic (EPA)-PE and arachidonic acid (ARA)-PE, with the latter predominating in ASCVD. This study investigated whether the association of PE (36:5) with ASCVD might result from an impairment of the antiatherogenic functions of HDL.Methods and resultsTotal PE and PE (36:5) content of large HDL isolated from 86 women with metabolic syndrome was positively associated with carotid intima-media thickness in multivariate regression analysis adjusted for traditional risk factors. In TgCETP x Ldlr-/- mice fed a high-cholesterol diet, the atherosclerotic plaque size was greater when reconstituted HDL (rHDL) containing ARA-PE was injected retro-orbitally, compared with injection of control rHDL containing only phosphatidylcholine (PC). In vitro, PE rHDL showed reduced cholesterol efflux capacity and impaired anti-inflammatory activity in THP-1 macrophages, together with diminished anti-oxidative activity against LDL oxidation compared to control rHDL. Strikingly, ARA-PE rHDL profoundly weakened of the HDL functions, while EPA-PE counteracted the ARA-PE-induced dysfunction and potentiated the functionality of rHDL.ConclusionsThis study reveals a causal link between PE species, particularly ARA-PE, and HDL dysfunction, contributing to atherosclerosis. EPA-PE can restore HDL function, supporting the therapeutic potential of EPA reducing ASCVD risk.