Increased atherosclerosis and expression of inflammarafts in macrophage foam cells in AIBP-deficient mice.

Scientific Reports · 2026-02-07

Abstract Atherosclerotic lesions comprise different populations of macrophages, including lipid-laden macrophage foam cells and non-foamy, inflammatory macrophages, which play distinct roles in disease progression. Non-foamy macrophages express higher levels of inflammarafts – enlarged, cholesterol-rich lipid rafts hosting assemblies of inflammatory receptors – compared to foam cells in atherosclerotic lesions of Ldlr −/− mice. Apolipoprotein A-I binding protein (AIBP) has been shown to control lipid raft dynamics. This study investigated the effect of systemic AIBP deficiency on inflammaraft expression in foam cells and non-foamy macrophages in atherosclerotic lesions of hypercholesterolemic mice. A larger number of foam cells, with increased neutral lipid accumulation, populated atherosclerotic lesions in Apoa1bp −/− Ldlr −/− mice compared to Ldlr −/− mice. Importantly, AIBP-deficient foam cells expressed higher levels of TLR4 dimers and lipid rafts (markers of inflammarafts) than control mice, accompanied by larger atherosclerotic lesions and larger necrotic cores compared to Ldlr −/− mice. In a model of foam cells, Apoa1bp −/− bone marrow-derived macrophages incubated with oxidized LDL had increased expression of inflammation and atherosclerosis related genes. These results indicate that AIBP deficiency results in a phenotype shift in foam cells, characterized by increased lipid accumulation and increased expression of inflammarafts, and it correlates with the development of advanced atherosclerotic plaques.

Halofuginone suppresses hepcidin by a heparan sulfate-dependent mechanism to treat iron disorders in mice

Blood Advances · 2026-02-11 · 1 citations

ABSTRACT: Hepcidin, a liver-derived hormone, is the central regulator of systemic iron homeostasis. Elevated hepcidin levels contribute to iron-refractory iron-deficiency anemia and anemia of inflammation, both characterized by restricted iron availability. Current treatments, such as parenteral iron infusions, are often ineffective and pose risks of adverse reactions, underscoring the need for alternative therapeutic strategies targeting hepcidin. We previously identified a novel hepcidin regulatory pathway involving liver heparan sulfate (HS) proteoglycans (HSPGs), which modulate receptor-ligand interactions through their sulfated HS chains. Recently, we found that halofuginone (HF) impairs HS biosynthesis and considered whether it could be used as a hepcidin modulator. Here, we demonstrate that in human hepatoma (Hep3B) cells, HF inhibits both basal and bone morphogenetic protein 6-induced hepcidin expression and SMAD1 phosphorylation signaling in a dose- and time-dependent manner. Consistently, Hep3B cells lacking HS (EXT1-/-) show no hepcidin suppression in response to HF. In vivo administration of HF reduces hepcidin expression in an iron-overload mouse model (8.3 g/kg carbonyl iron). This effect was absent in mice with impaired liver HS sulfation (Ndst1f/fAlbCre+), confirming that HF suppresses hepcidin via HSPG-mediated mechanisms. Additionally, HF decreased hepcidin expression in mice subjected to acute inflammation. These findings establish HF as a potential therapeutic for mitigating hepcidin-driven iron restriction in anemic disorders.

High-Density Lipoproteins Associated with Age-Related Macular Degeneration in the All of Us Research Program

Ophthalmology · 2025-01-04 · 11 citations

PURPOSE: Extracellular lipoprotein aggregation is a critical event in age-related macular degeneration (AMD) pathogenesis. In this study, we sought to analyze associations between clinical and genetic-based factors related to lipoprotein metabolism and risk for AMD in the All of Us research program. DESIGN: Cross-sectional retrospective data analysis. PARTICIPANTS: A total of 5028 healthy participants and 2328 patients with AMD from All of Us. METHODS: Participants with and without AMD were age, race, and sex matched in a 1:2 ratio, respectively. Smoking status, history of hyperlipidemia, and statin use were extracted in a binary manner. Statin use was further subcategorized into hepatically versus nonhepatically metabolized statins. Laboratory values for low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TGs) were also extracted, and outliers were excluded from analysis. The PLINK toolkit was used to extract single nucleotide polymorphisms (SNPs) associated with LDL and HDL dysregulation, as published in prior work. Odds ratio curves were computed to assess the risk between LDL, TG, and HDL versus AMD. All clinical and genetic variables were input into a multivariable logistic regression model, and odds ratios and P values were generated. MAIN OUTCOME MEASURES: Statistical significance of risk factors for AMD, thresholded at P ≤ 0.05. RESULTS: On multivariable regression analysis, statin use and low and high HDL were significantly associated with increased AMD risk (P < 0.001 for all variables). Additionally, the multivariable regression implicated HDL-associated SNP's increased risk for AMD. Last, LPA was identified (P = 0.007) as a novel SNP associated with increased AMD risk. CONCLUSIONS: There exists a U-shaped relationship between HDL and AMD risk, such that high and low HDL are significantly associated with increased AMD risk. Additionally, SNPs associated with HDL metabolism are associated with AMD risk. This analysis further establishes the role of HDL in AMD pathogenesis. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Bruch’s membrane heparan sulfate retains lipoproteins in the early stages of age-related macular degeneration

Proceedings of the National Academy of Sciences · 2025-06-13 · 5 citations

Lipoprotein retention in Bruch's membrane is a key event in the pathobiology of early and intermediate age-related macular degeneration (AMD). However, the mechanism of lipoprotein retention in BrM is unknown. Given the established role of glycosaminoglycans (GAG) in binding lipoproteins, our laboratory sought to determine the role of GAGs in AMD BrM. In this study, BrM GAG content in AMD pathobiology was analyzed in human postmortem tissue. Strikingly, increased levels of highly sulfated heparan sulfate were present in AMD Bruch's membrane as compared to non-AMD samples. In addition, using scanning electron microscopy of postmortem AMD tissue, we show aggregates of lipoprotein-like particles on the retinal pigmented epithelium side of Bruch's membrane adjacent to heparan sulfate. We also show that heparin displaces lipoproteins rich in apolipoprotein A1 from human BrM, suggesting their identity as high-density lipoproteins. Using human BrM immobilized to quartz crystal microbalance biosensor (QCM) chips, we show that heparan sulfate is required for lipoprotein binding to BrM and soluble heparan sulfate can remove lipoproteins bound to BrM. Thus, our data establish that heparan sulfate regulates lipoprotein deposition in AMD BrM. These findings provide a foundation for targeted therapies capable of either preventing lipoprotein accumulation or removing drusen in the early and intermediate stages of AMD prior to vision loss.

Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections

Immunity · 2025-07-17 · 5 citations

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Ophthalmology · 2025-09-26

Increased atherosclerosis and expression of inflammarafts in macrophage foam cells in AIBP-deficient mice

bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-15

Background: Atherosclerotic lesions comprise different populations of macrophages, including lipid-laden macrophage foam cells and non-foamy, inflammatory macrophages, playing different roles in disease progression. Previous studies demonstrated higher expression of inflammarafts - enlarged, cholesterol-rich lipid rafts hosting assemblies of inflammatory receptors - in non-foamy, inflammatory macrophages, as opposed to lower inflammarafts in lipid-lade macrophage foam cells. Apolipoprotein A-I Binding Protein (AIBP) facilitates cholesterol efflux from macrophages and has been shown to reduce inflammatory responses and protect against atherosclerosis. This study investigated the effect of AIBP deficiency on inflammaraft expression in aortic foam cells and non-foamy macrophages in hypercholesterolemic mice. Methods: macrophages were gated for BODIPY-high foamy and BODIPY-low non-foamy cells and analyzed for the expression of inflammaraft markers TLR4 (toll-like receptor-4) dimers and lipid rafts. Consecutive sections of the aortic root were stained with modified Van Gieson stain to assess lesion and necrotic core sizes. Results: mice. Male and female mice showed similar results. Conclusions: Our results indicate that AIBP deficiency leads to the formation of a new foam cell phenotype in which the increased lipid accumulation is associated with an increased expression of TLR4 inflammarafts. This transition of foam cells to a proinflammatory phenotype correlates with the development of advanced atherosclerotic plaques.

LDL-Bound PCSK9 Has a Slower Clearance Kinetic and Higher Use for HSPGs Than Free-PCSK9—Brief Report

Arteriosclerosis Thrombosis and Vascular Biology · 2025-07-03 · 1 citations

BACKGROUND: Hepatic heparan sulfate proteoglycans (HSPGs) accelerate the clearance of PCSK9 (proprotein convertase subtilisin/kexin type 9). We tested the hypothesis that free- and LDL (low-density lipoprotein)–bound PCSK9 forms have different HSPG-mediated clearance kinetics. METHODS: Metabolic and turnover studies were performed after administration of free- and LDL-bound PCSK9 to 2 HSPG knockout mouse models: (1) Global knockout of syndecan-1 ( Sdc1 −/ − ), an HSPG involved in hepatic triglyceride clearance; and (2) hepatocyte-specific knockout of heparan sulfate N-deacetylase/N-sulfotransferase (AlbCre + Ndst1 f/f ). RESULTS: The clearance of both free- and LDL-bound PCSK9 followed a 2-phase decay behavior comprising a fast and a slow phase. The more notorious effect of HSPG deletion was on the slow phase: the clearance of free-PCSK9 was faster in Sdc1 −/ − mice (t 1/2,slow [half-life on the slow phase] 13.5±1.5 minutes; P =0.0305) than in wild-type (t 1/2,slow 28.8±4.2 minutes) and AlbCre + Ndst1 f/f mice (t 1/2,slow 32.7±4.9 minutes). The clearance of LDL-bound PCSK9 was slower yet not statistically significant in Sdc1 −/ − mice (t 1/2,slow 111.2±21.6 minutes) than in wild-type (t 1/2,slow 52±6.4 minutes) and AlbCre + Ndst1 f/f mice (t 1/2,slow 39.55±2.96 minutes). However, the area under the curve showed a delayed clearance of LDL-bound PCSK9 in Sdc1 −/ − mice (44 576±2435 min×ng, P =0.004) but not in AlbCre + Ndst1 f/f (34 738±3721 min×ng, P =0.578) mice compared with wild-type (30 865±1907 min×ng). Hepatic Ndst1 -deficiency did not alter hepatic PCSK9 or LDLR (LDL receptor) expression. CONCLUSIONS: The clearance rate of plasma LDL-bound PCSK9 is slower than the clearance rate of its free form. The HSPG syndecan-1 modestly contributes to PCSK9 clearance through an LDLR-independent pathway.

Adipocyte heparan sulfate determines type 2 diabetes susceptibility in mice via FGF1-Mediated glucose regulation

Molecular Metabolism · 2025-10-09

Obesity is the principal driver of insulin resistance, and lipodystrophy is also linked with insulin resistance, emphasizing the vital role of adipose tissue in glucose homeostasis. The quality of adipose tissue expansion is a critical determinant of insulin resistance predisposition, with individuals suffering from metabolic unhealthy adipose expansion exhibiting greater risk. Adipocytes are pivotal in orchestrating metabolic adjustments in response to nutrient intake and cell intrinsic factors that positively regulate these adjustments are key to prevent Type-2 diabetes. Employing unique genetic mouse models, we established the critical involvement of heparan sulfate (HS), a fundamental element of the adipocyte glycocalyx, in upholding glucose homeostasis during dietary stress. Genetic models that compromise adipocyte HS accelerate the development of high-fat diet-induced hyperglycemia and insulin resistance, independent of weight gain. Mechanistically, we show that perturbations in adipocyte HS disrupts endogenous FGF1 signaling, a key nutrient-sensitive effector. Furthermore, compromising adipocyte HS composition detrimentally impacts FGF1-FGFR1-mediated endocrinization, with no significant improvement observed in glucose homeostasis. Our data establish adipocyte HS composition as a determinant of Type 2 diabetes susceptibility and the critical dependency of the endogenous adipocyte FGF1 metabolic pathway on HS. • Adipocyte heparan sulfate does not impact diet-induced weight gain. • Adipocyte heparan sulfate sulfation compromises glucose regulation and insulin sensitivity under nutrient stress. • Mice with reduced HS sulfation show increased insulin resistance and fatty liver disease in a diet-induced obesity model. • Mechanistically HS sulfation is essential for the glucose-lowering effect of FGF1, a critical paracrine insulin sensitizer in adipose tissue.

Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis

Cell Metabolism · 2024-11-14 · 35 citations

mice accelerated hepatic very-low-density lipoprotein (VLDL) and sphingolipid secretion into circulation to promote atherogenesis compared with a cis-unsaturated fatty acid (CFA)-enriched HFD. SPT inhibition mitigated these phenotypes and reduced circulating atherogenic VLDL enriched in TFA-derived polyunsaturated sphingomyelin. Transcriptional analysis of human liver revealed distinct regulation of SPTLC2 versus SPTLC3 subunit expression, consistent with human genetic correlations in ASCVD, further establishing sphingolipid metabolism as a critical node mediating the progression of ASCVD in response to specific dietary fats.