RARE DISEASE
Apolipoprotein A-I deficiency
Apolipoprotein A-I deficiency
Apolipoprotein A-I deficiency
Synonyms: ApoA-I deficiency, Familial apoA-I deficiency, Familial hypoalphalipoproteinemia
Synonyms: ApoA-I deficiency, Familial apoA-I deficiency, Familial hypoalphalipoproteinemia
Synonyms: ApoA-I deficiency, Familial apoA-I deficiency, Familial hypoalphalipoproteinemia
Drug discovery
1
drug
With orphan designation
Overview
Apolipoprotein A-I deficiency is a rare autosomal recessive disorder characterized by extremely low HDL cholesterol (<10 mg/dL) and ApoA-I levels (<20 mg/dL) due to pathogenic APOA1 gene variants. Impaired cholesterol efflux increases coronary artery disease (CAD) risk, often manifesting as premature CAD (before age 50), corneal opacities, and xanthomas. Associated systemic amyloidosis or neurological symptoms occur in some mutations. Diagnosis requires genetic confirmation and differentiation from other HDL deficiencies (e.g., Tangier disease) [1][6][11].
Burden
Premature CAD (e.g., myocardial infarction in mid-30s) and recurrent events requiring intervention [2][6][16].
Heterogeneity: Some mutations cause amyloidosis (hepatic, renal, or cardiac failure); others present asymptomatically [6][11].
Lifetime management costs due to chronic CVD monitoring and advanced therapies (e.g., gene therapy) [1][3][18].
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism
Research Papers
329 drug discovery papers about Apolipoprotein A-I deficiency, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
329 drug discovery papers about Apolipoprotein A-I deficiency, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-08-30 | Apolipoprotein A (ApoA) in Neurological Disorders: Connections and Insights.
Apolipoprotein A (ApoA) proteins, ApoA-I, ApoA-II, ApoA-IV, and ApoA-V, play critical roles in lipid metabolism, neuroinflammation, and blood-brain barrier integrity, making them pivotal in neurological diseases such as Alzheimer's disease (AD), stroke, Parkinson's disease (PD), and multiple sclerosis (MS). This review synthesizes current evidence on their structural and functional contributions to neuroprotection, highlighting their dual roles as biomarkers and therapeutic targets. ApoA-I, the most extensively studied, exhibits anti-inflammatory, antioxidant, and amyloid-clearing properties, with reduced levels associated with AD progression and cognitive decline. ApoA-II modulates HDL metabolism and stroke risk, while ApoA-IV influences neuroinflammation and amyloid processing. ApoA-V, although less explored, is implicated in stroke susceptibility through its regulation of triglycerides. Genetic polymorphisms (e.g., APOA1 rs670, APOA5 rs662799) further complicate disease risk, showing population-specific associations with stroke and neurodegeneration. Therapeutic strategies targeting ApoA proteins, including reconstituted HDL, mimetic peptides, and gene-based approaches, show promise in preclinical models but face translational challenges in human trials. Clinical trials, such as those with CSL112, highlight the need for neuro-specific optimization. Further research should prioritize human-relevant models, advanced neuroimaging techniques, and functional assays to elucidate ApoA mechanisms inside the central nervous system. The integration of genetic, lipidomic, and clinical data offers potential for enhancing precision medicine in neurological illnesses by facilitating the generation of ApoA-targeted treatments and bridging current deficiencies in disease comprehension and therapy.
2025-03-15 | The lack of apoA-I in apoE-KO mice affects the liver transcriptome.
Liver is the major organ involved in apoA-I synthesis and HDL-C turnover, but the impact of apoA-I/HDL on hepatic transcriptome has never been investigated before. In the present study, a transcriptomic analysis by high-throughput RNA-seq was conducted in the liver of atherosclerosis-prone mice, with the aim of identifying new genes/pathways modulated by apoA-I/HDL with a potential effect on atherosclerosis development. Eight-week-old apoE knockout (apoEKO) mice lacking apoA-I/HDL (DKO) and with physiological levels of apoA-I/HDL (DKO/hA-I) were fed either a standard rodent diet (SRD) or a Western diet (WD) for 22 weeks. After both dietary treatments, DKO mice were characterized by lower cholesterol levels, but increased atherosclerosis development, compared to DKO/hA-I mice. The liver transcriptome of DKO and DKO/hA-I mice fed SRD diverged in a relatively small number of genes, suggestive of a greater activation of the PPAR signaling pathway and the retinoid metabolism pathway in DKO/hA-I mice. Following WD, transcriptomic analysis highlighted in both genotypes an upregulated expression of immune/inflammatory genes and a reduced activation of the retinoid metabolism. The evaluation of the hepatic response of the two genotypes to the dietary switch from SRD to WD revealed strong divergences in genes involved in metabolic pathways only in the presence of apoA-I/HDL, with reduced endogenous sterol biosynthesis and glutathione metabolism, together with increased glucose metabolism. The presence or absence of apoA-I expression differently alters hepatic pathways involved not only in cholesterol metabolism, but also in those of glutathione and glucose metabolism.
2024-10-16 | Apolipoprotein A-I Mimetic Peptide Restores VEGF-induced Angiogenesis in Hypercholesterolemic Ischemic Heart by Reducing HDL Proinflammatory Properties.
VEGF-induced angiogenesis is impaired in hypercholesterolemia. Previous studies showed that an apolipoprotein A-I(ApoA-I) mimetic peptide, D-4F, is able to reduce HDL proinflammatory index in hypercholesterolemia. Whether D-4F promotes angiogenesis in hypercholesterolemia remains unclear. Low-density lipoprotein receptor null (LDLr-/-) mice and LDLr-/-/ApoA-I-/- mice were fed with high-fat diet with or without D-4F (1mg/kg·d). C57BL/6 mice fed with normal diet served as control. The myocardial infarction was induced by ligation coronary artery, and the VEGFA-AAV 9 was injected in heart. The plasma HDL proinflammatory index, cardiac function, infarct size, and angiogenesis related signaling pathways were examined. The HDL proinflammatory index increases in hypercholesterolemic mice. VEGFA stimulates angiogenesis and improves cardiac function in ischemic heart of C57BL/6 mice, but not in hypercholesterolemic mice. D-4F reduces HDL proinflammatory index. D-4F combined with VEGFA stimulates the expression of CD31 and eNOS, activates ERK1/2, reduces infarct size, and improves cardiac function in ischemic heart in hypercholesterolemic LDLr-/- mice but not in hypercholesterolemic LDLr-/-/ApoA-I-/- mice. D-4F restores the VEGF-induced angiogenesis by reducing HDL proinflammatory properties in hypercholesterolemic ischemic heart.
2024-03-19 | Apolipoprotein A-1 Accelerated Liver Regeneration Through Regulating Autophagy Via AMPK-ULK1 Pathway.
Apolipoprotein A-1 (ApoA-1), the main apolipoprotein of high-density lipoprotein, has been well studied in the area of lipid metabolism and cardiovascular diseases. In this project, we clarify the function and mechanism of ApoA-1 in liver regeneration. Seventy percent of partial hepatectomy was applied in male ApoA-1 knockout mice and wild-type mice to investigate the effects of ApoA-1 on liver regeneration. D-4F (ApoA-1 mimetic peptide), autophagy activator, and AMPK activator were used to explore the mechanism of ApoA-1 on liver regeneration. We demonstrated that ApoA-1 levels were highly expressed during the early stage of liver regeneration. ApoA-1 deficiency greatly impaired liver regeneration after hepatectomy. Meanwhile, we found that ApoA-1 deficiency inhibited autophagy during liver regeneration. The activation of autophagy protected against ApoA-1 deficiency in inhibiting liver regeneration. Furthermore, ApoA-1 deficiency impaired autophagy through AMPK-ULK1 pathway, and AMPK activation significantly improved liver regeneration. The administration of D-4F could accelerated liver regeneration after hepatectomy. These findings suggested that ApoA-1 played an essential role in liver regeneration through promoting autophagy in hepatocytes via AMPK-ULK1 pathway. Our findings enrich the understanding of the underlying mechanism of liver regeneration and provide a potential therapeutic strategy for liver injury.
2023-01-03 | Apolipoprotein A-1 protected hepatic ischaemia-reperfusion injury through suppressing macrophage pyroptosis via TLR4-NF-κB pathway.
Apolipoprotein A-1 (ApoA-1), the major apolipoprotein of high-density lipoprotein, plays anti-atherogenic role in cardiovascular diseases and exerts anti-inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA-1 in hepatic ischaemia-reperfusion (I/R) injury is unknown. In this study, we measured ApoA-1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA-1 knockout mice, ApoA-1 mimetic peptide D-4F treatment mice and corresponding control mice to examine the effect of ApoA-1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study. The results showed that ApoA-1 expression was down-regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA-1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA-1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA-1 deficiency. Furthermore, the up-regulated pyroptosis process was testified to be mediated by ApoA-1 through TLR4-NF-κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D-4F ameliorated hepatic I/R injury. Our study has identified the protective role of ApoA-1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4-NF-κB pathway. The effect of ApoA-1 may provide a novel therapeutic approach for hepatic I/R injury.
small molecules
2025-11-22 | Loss of GPR146 decreases plasma levels of HDL cholesterol via post-translational up-regulation of SR-B1 protein levels.
In humans, reduced G-protein coupled receptor 146 (GPR146) expression is associated with reductions in both LDL and HDL cholesterol. While the effects on LDL cholesterol are mediated via the intracellular ERK/SREBP2 pathway, the mechanism explaining how GPR146 affects HDL cholesterol levels remains to be unravelled. Whole-body (Gpr146-/-) and liver-specific Gpr146 knockout (Gpr146 LKO) mice were used to explore changes in HDL metabolism. Wild-type mice were treated with a MEK1 inhibitor to block ERK signalling. HDL uptake and post-translational modification of scavenger receptor class B1 (SR-B1) were studied in murine primary hepatocytes. Genetic variants in GPR146 and SCARB1 served as instruments to examine HDL size and composition in human cohort studies. Investigation in both Gpr146-/- and Gpr146 LKO mice revealed a 20% reduction in HDL cholesterol and a concomitant 30% increase in hepatic SR-B1 protein (without changes in Scarb1 mRNA). This increase was driven by a 2.2-fold increase in cell surface SR-B1 via a mechanism that appears independent of ERK. In vitro studies show that loss of GPR146 increases SR-B1-mediated selective uptake of HDL lipid and HDL protein. Consistently, carriers of a GPR146 variant associated with loss-of-function and carriers of SCARB1 gain-of-function variant share reductions in apoA-I, HDL particle size, HDL cholesterol, and cholesteryl ester content compared to non-carriers. This study suggests that loss of GPR146 reduces HDL cholesterol via post-translational up-regulation of hepatic SR-B1 via an intracellular pathway that remains to be resolved. These findings imply that GPR146 inhibition to treat hypercholesterolaemia may not only lower plasma levels of LDL cholesterol but also HDL cholesterol.
2025-09-01 | Effect of Extra Virgin Olive Oil High in Bioactive Compounds on Atherosclerosis in Apoe-Deficient Mice.
To test the effects of extra virgin olive oil (EVOO) enriched in specific bioactive compounds (EVOO HBC) on atherosclerosis and fatty liver, three isocaloric Western diets differing in the type of fat (palm, EVOO, or EVOO HBC) were fed to Apoe-deficient mice for 12 weeks. Plasma lipids, lipoprotein characterization, circulating CD36-expressing monocytes, and M2 peritoneal macrophages were quantified. Hepatic squalene and cross-sectional and en face atherosclerotic lesions were analyzed. Compared to the palm group, plasma triglyceride and glucose levels increased, while APOA1, paraoxonase 1 activity, and lipoprotein oxidation decreased in mice fed both EVOO groups. The latter stored liver squalene according to the amount consumed. En face and cross-sectional atherosclerotic lesions were lower in the EVOO groups. CD36 expression in circulating monocytes was lower and M2 peritoneal macrophages were higher in the EVOO groups. In males, there was a reduced presence of CD68-expressing cells in atherosclerotic plaques, while in females, there was a reduction in en face lesions that negatively correlated with high-density lipoprotein (HDL)-phospholipid efflux. The recruitment of macrophages into atherosclerotic plaques and the improvement of HDL efflux may be sex-dependent and attributable to the high content of squalene and a specific oleuropein aglycone.
2024-03-06 | Flipped C-Terminal Ends of APOA1 Promote ABCA1-Dependent Cholesterol Efflux by Small HDLs.
Cholesterol efflux capacity (CEC) predicts cardiovascular disease independently of high-density lipoprotein (HDL) cholesterol levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 (ATP-binding cassette transporter A1) pathway, but the underlying mechanisms are unclear. We used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)-deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of APOA1 (apolipoprotein A1) in the different particles, and the CECs of plasma and isolated HDLs. We quantified macrophage and ABCA1 CEC of 4 distinct sizes of reconstituted HDL. CEC increased as particle size decreased. Tandem mass spectrometric analysis of chemically cross-linked peptides and molecular dynamics simulations of APOA1, the major protein of HDL, indicated that the mobility of C-terminus of that protein was markedly higher and flipped off the surface in the smallest particles. To explore the physiological relevance of the model system studies, we isolated HDL from LCAT-deficient subjects, whose small HDLs (like reconstituted HDLs) are discoidal and composed of APOA1, cholesterol, and phospholipid. Despite their very low plasma levels of HDL particles, these subjects had normal CEC. In both the LCAT-deficient subjects and control subjects, the CEC of isolated extra-small HDL (a mixture of extra-small and small HDL by calibrated ion mobility analysis) was 3- to 5-fold greater than that of the larger sizes of isolated HDL. Incubating LCAT-deficient plasma and control plasma with human LCAT converted extra-small and small HDL particles into larger particles, and it markedly inhibited CEC. We present a mechanism for the enhanced CEC of small HDLs. In smaller particles, the C-termini of the 2 antiparallel molecules of APOA1 are "flipped" off the lipid surface of HDL. This extended conformation allows them to engage with ABCA1. In contrast, the C-termini of larger HDLs are unable to interact productively with ABCA1 because they form a helical bundle that strongly adheres to the lipid on the particle. Enhanced CEC, as seen with the smaller particles, predicts decreased cardiovascular disease risk. Thus, extra-small and small HDLs may be key mediators and indicators of the cardioprotective effects of HDL.
2023-12-03 | Functional characterization of missense variants affecting the extracellular domains of ABCA1 using a fluorescence-based assay
Excess cholesterol originating from nonhepatic tissues is transported within HDL particles to the liver for metabolism and excretion. Cholesterol efflux is initiated by lipid-free or lipid-poor apolipoprotein A1 interacting with the transmembrane protein ABCA1, a key player in cholesterol homeostasis. Defective ABCA1 results in reduced serum levels of HDL cholesterol, deposition of cholesterol in arteries, and an increased risk of early onset CVD. Over 300 genetic variants in ABCA1 have been reported, many of which are associated with reduced HDL cholesterol levels. Only a few of these have been functionally characterized. In this study, we have analyzed 51 previously unclassified missense variants affecting the extracellular domains of ABCA1 using a sensitive, easy, and low-cost fluorescence-based assay. Among these, only 12 variants showed a distinct loss-of-function phenotype, asserting their direct association with severe HDL disorders. These findings emphasize the crucial role of functional characterization of genetic variants in pathogenicity assessment and precision medicine. The functional rescue of ABCA1 loss-of-function variants through proteasomal inhibition or by the use of the chemical chaperone 4-phenylbutyric acid was genotype specific. Genotype-specific responses were also observed for the ability of apolipoprotein A1 to stabilize the different ABCA1 variants. In view of personalized medicine, this could potentially form the basis for novel therapeutic strategies.
2023-07-13 | Sulforaphane Inhibits Foam Cell Formation and Atherosclerosis via Mechanisms Involving the Modulation of Macrophage Cholesterol Transport and the Related Phenotype.
Sulforaphane (SFN), an isothiocyanate, is one of the major dietary phytochemicals found in cruciferous vegetables. Many studies suggest that SFN can protect against cancer and cardiometabolic diseases. Despite the proposed systemic and local vascular protective mechanisms, SFN's potential to inhibit atherogenesis by targeting macrophages remains unknown. In this study, in high fat diet fed ApoE-deficient (ApoE-/-) mice, oral SFN treatment improved dyslipidemia and inhibited atherosclerotic plaque formation and the unstable phenotype, as demonstrated by reductions in the lesion areas in both the aortic sinus and whole aorta, percentages of necrotic cores, vascular macrophage infiltration and reactive oxygen species (ROS) generation. In THP-1-derived macrophages, preadministration SFN alleviated oxidized low-density lipoprotein (ox-LDL)-induced lipid accumulation, oxidative stress and mitochondrial injury. Moreover, a functional study revealed that peritoneal macrophages isolated from SFN-treated mice exhibited attenuated cholesterol influx and enhanced apolipoprotein A-I (apoA-I)- and high-density lipoprotein (HDL)-mediated cholesterol efflux. Mechanistic analysis revealed that SFN supplementation induced both intralesional and intraperitoneal macrophage phenotypic switching toward high expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and ATP-binding cassette subfamily A/G member 1 (ABCA1/G1) and low expression of peroxisome proliferator-activated receptor γ (PPARγ) and cluster of differentiation 36 (CD36), which was further validated by the aortic protein expression. These results suggest that the regulation of macrophages' cholesterol transport and accumulation may be mainly responsible for SFN's potential atheroprotective properties, and the regulatory mechanisms might involve upregulating ABCA1/G1 and downregulating CD36 via the modulation of PPARγ and Nrf2.
gene therapies
2025-11-27 | From HDL Deficiency to Neuropathy: Insights into Tangier Disease
Introduction: This review aims to provide a comprehensive examination of Tangier disease, focusing on its clinical manifestations, pathophysiology, and diagnostic methods. The article also delves into the available management strategies, the challenges in treating this rare condition, and the ongoing research into potential therapeutic interventions. Materials and Methods: A comprehensive review of the literature was conducted using the PubMed and Google Scholar databases with the following keywords: "Tangier disease", "HDL deficiency", "ABCA1", "neuropathy", "high-density lipoprotein ", "HDL", "apoA-I", "CETP", "atherosclerosis", "splenomegaly". Summary: Tangier disease is a rare autosomal recessive genetic disorder caused by mutations in the ABCA1 gene, which impairs cholesterol transport and results in low levels of HDL. This leads to the accumulation of cholesterol esters in various tissues, including the tonsils, spleen, lymph nodes, and nerves. The disease is characterized by orange-colored, enlarged tonsils, splenomegaly, peripheral neuropathy, and a heightened risk for atherosclerotic cardiovascular disease. Diagnosis is confirmed through low HDL and apoA-I levels, along with genetic testing for ABCA1 mutations. While no cure exists, treatment focuses on symptom management, controlling cardiovascular risks, and improving HDL function through lifestyle and dietary changes. Conclusions: Tangier disease, a rare genetic disorder caused by mutations in the ABCA1 gene, leads to severe lipid imbalances and various systemic complications. Although there is no cure, managing symptoms, controlling cardiovascular risks, and adopting lifestyle changes are essential for improving outcomes. Ongoing research into gene therapies and new treatments offers hope for future breakthroughs.
2022-06-24 | Lack of ApoA-I in ApoEKO Mice Causes Skin Xanthomas, Worsening of Inflammation, and Increased Coronary Atherosclerosis in the Absence of Hyperlipidemia.
HDL (high-density lipoprotein) and its major protein component, apoA-I (apolipoprotein A-I), play a unique role in cholesterol homeostasis and immunity. ApoA-I deficiency in hyperlipidemic, atheroprone mice was shown to drive cholesterol accumulation and inflammatory cell activation/proliferation. The present study was aimed at investigating the impact of apoA-I deficiency on lipid deposition and local/systemic inflammation in normolipidemic conditions. ApoE deficient mice, apoE/apoA-I double deficient (DKO) mice, DKO mice overexpressing human apoA-I, and C57Bl/6J control mice were fed normal laboratory diet until 30 weeks of age. Plasma lipids were quantified, atherosclerosis development at the aortic sinus and coronary arteries was measured, skin ultrastructure was evaluated by electron microscopy. Blood and lymphoid organs were characterized through histological, immunocytofluorimetric, and whole transcriptome analyses. DKO were characterized by almost complete HDL deficiency and by plasma total cholesterol levels comparable to control mice. Only DKO showed xanthoma formation and severe inflammation in the skin-draining lymph nodes, whose transcriptome analysis revealed a dramatic impairment in energy metabolism and fatty acid oxidation pathways. An increased presence of CD4+ T effector memory cells was detected in blood, spleen, and skin-draining lymph nodes of DKO. A worsening of atherosclerosis at the aortic sinus and coronary arteries was also observed in DKO versus apoE deficient. Human apoA-I overexpression in the DKO background was able to rescue the skin phenotype and halt atherosclerosis development. HDL deficiency, in the absence of hyperlipidemia, is associated with severe alterations of skin morphology, aortic and coronary atherosclerosis, local and systemic inflammation.
2020-02-27 | Hepatic Forkhead Box Protein A3 Regulates ApoA-I (Apolipoprotein A-I) Expression, Cholesterol Efflux, and Atherogenesis.
To determine the role of hepatic FOXA3 (forkhead box A3) in lipid metabolism and atherosclerosis. Approach and Results: Hepatic FOXA3 expression was reduced in diabetic or high fat diet-fed mice or patients with nonalcoholic steatohepatitis. We then used adenoviruses to overexpress or knock down hepatic FOXA3 expression. Overexpression of FOXA3 in the liver increased hepatic ApoA-I (apolipoprotein A-I) expression, plasma HDL-C (high-density lipoprotein cholesterol) level, macrophage cholesterol efflux, and macrophage reverse cholesterol transport. In contrast, knockdown of hepatic FOXA3 expression had opposite effects. We further showed that FOXA3 directly bound to the promoter of the Apoa1 gene to regulate its transcription. Finally, AAV8 (adeno-associated virus serotype 8)-mediated overexpression of human FOXA3 in the hepatocytes of Apoe-/- (apolipoprotein E-deficient) mice raised plasma HDL-C levels and significantly reduced atherosclerotic lesions. Hepatocyte FOXA3 protects against atherosclerosis by inducing ApoA-I and macrophage reverse cholesterol transport.
2019-06-27 | AIBP protects against metabolic abnormalities and atherosclerosis.
Apolipoprotein A-I binding protein (AIBP) has been shown to augment cholesterol efflux from endothelial cells and macrophages. In zebrafish and mice, AIBP-mediated regulation of cholesterol levels in the plasma membrane of endothelial cells controls angiogenesis. The goal of this work was to evaluate metabolic changes and atherosclerosis in AIBP loss-of-function and gain-of-function animal studies. Here, we show that Apoa1bp-/-Ldlr-/- mice fed a high-cholesterol, high-fat diet had exacerbated weight gain, liver steatosis, glucose intolerance, hypercholesterolemia, hypertriglyceridemia, and larger atherosclerotic lesions compared with Ldlr-/- mice. Feeding Apoa1bp-/-Ldlr-/- mice a high-cholesterol, normal-fat diet did not result in significant differences in lipid levels or size of atherosclerotic lesions from Ldlr-/- mice. Conversely, adeno-associated virus-mediated overexpression of AIBP reduced hyperlipidemia and atherosclerosis in high-cholesterol, high-fat diet-fed Ldlr-/- mice. Injections of recombinant AIBP reduced aortic inflammation in Ldlr-/- mice fed a short high-cholesterol, high-fat diet. Conditional overexpression of AIBP in zebrafish also reduced diet-induced vascular lipid accumulation. In experiments with isolated macrophages, AIBP facilitated cholesterol efflux to HDL, reduced lipid rafts content, and inhibited inflammatory responses to lipopolysaccharide.jlr Our data demonstrate that AIBP confers protection against diet-induced metabolic abnormalities and atherosclerosis.
2019-01-07 | HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, PI3K-, and Akt-dependent manner.
Doxorubicin is a widely used chemotherapeutic with deleterious cardiotoxic side effects. HDL has been shown to protect cardiomyocytes in vitro against doxorubicin-induced apoptosis. Scavenger receptor class B type 1 (SR-B1), a high-affinity HDL receptor, mediates cytoprotective signaling by HDL through Akt. Here, we assessed whether increased HDL levels protect against doxorubicin-induced cardiotoxicity in vivo and in cardiomyocytes in culture and explored the intracellular signaling mechanisms involved, particularly the role of SR-B1. Transgenic mice with increased HDL levels through overexpression of human apolipoprotein A1 (apoA1Tg/Tg) and wild-type mice (apoA1+/+) with normal HDL levels were treated repeatedly with doxorubicin. After treatment, apoA1+/+ mice displayed cardiac dysfunction, as evidenced by reduced left ventricular end-systolic pressure and +dP/d t, and histological analysis revealed cardiomyocyte atrophy and increased cardiomyocyte apoptosis after doxorubicin treatment. In contrast, apoA1Tg/Tg mice were protected against doxorubicin-induced cardiac dysfunction and cardiomyocyte atrophy and apoptosis. When SR-B1 was knocked out, however, overexpression of apoA1 did not protect against doxorubicin-induced cardiotoxicity. Using primary neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes in combination with genetic knockout, inhibitors, or siRNA-mediated knockdown, we demonstrated that SR-B1 is required for HDL-mediated protection of cardiomyocytes against doxorubicin-induced apoptosis in vitro via a pathway involving phosphatidylinositol 3-kinase and Akt1/2. Our findings provide proof of concept that raising apoA1 to supraphysiological levels can dramatically protect against doxorubicin-induced cardiotoxicity via a pathway that is mediated by SR-B1 and involves Akt1/2 activation in cardiomyocytes. NEW & NOTEWORTHY We have identified an important role for the scavenger receptor class B type 1 in facilitating high-density lipoprotein-mediated protection of cardiomyocytes against stress-induced apoptosis and shown that increasing plasma high-density lipoprotein protects against the deleterious side effects of the chemotherapeutic and cardiotoxic drug doxorubicin.
proteins
2025-08-30 | Apolipoprotein A (ApoA) in Neurological Disorders: Connections and Insights.
Apolipoprotein A (ApoA) proteins, ApoA-I, ApoA-II, ApoA-IV, and ApoA-V, play critical roles in lipid metabolism, neuroinflammation, and blood-brain barrier integrity, making them pivotal in neurological diseases such as Alzheimer's disease (AD), stroke, Parkinson's disease (PD), and multiple sclerosis (MS). This review synthesizes current evidence on their structural and functional contributions to neuroprotection, highlighting their dual roles as biomarkers and therapeutic targets. ApoA-I, the most extensively studied, exhibits anti-inflammatory, antioxidant, and amyloid-clearing properties, with reduced levels associated with AD progression and cognitive decline. ApoA-II modulates HDL metabolism and stroke risk, while ApoA-IV influences neuroinflammation and amyloid processing. ApoA-V, although less explored, is implicated in stroke susceptibility through its regulation of triglycerides. Genetic polymorphisms (e.g., APOA1 rs670, APOA5 rs662799) further complicate disease risk, showing population-specific associations with stroke and neurodegeneration. Therapeutic strategies targeting ApoA proteins, including reconstituted HDL, mimetic peptides, and gene-based approaches, show promise in preclinical models but face translational challenges in human trials. Clinical trials, such as those with CSL112, highlight the need for neuro-specific optimization. Further research should prioritize human-relevant models, advanced neuroimaging techniques, and functional assays to elucidate ApoA mechanisms inside the central nervous system. The integration of genetic, lipidomic, and clinical data offers potential for enhancing precision medicine in neurological illnesses by facilitating the generation of ApoA-targeted treatments and bridging current deficiencies in disease comprehension and therapy.
2025-03-15 | The lack of apoA-I in apoE-KO mice affects the liver transcriptome.
Liver is the major organ involved in apoA-I synthesis and HDL-C turnover, but the impact of apoA-I/HDL on hepatic transcriptome has never been investigated before. In the present study, a transcriptomic analysis by high-throughput RNA-seq was conducted in the liver of atherosclerosis-prone mice, with the aim of identifying new genes/pathways modulated by apoA-I/HDL with a potential effect on atherosclerosis development. Eight-week-old apoE knockout (apoEKO) mice lacking apoA-I/HDL (DKO) and with physiological levels of apoA-I/HDL (DKO/hA-I) were fed either a standard rodent diet (SRD) or a Western diet (WD) for 22 weeks. After both dietary treatments, DKO mice were characterized by lower cholesterol levels, but increased atherosclerosis development, compared to DKO/hA-I mice. The liver transcriptome of DKO and DKO/hA-I mice fed SRD diverged in a relatively small number of genes, suggestive of a greater activation of the PPAR signaling pathway and the retinoid metabolism pathway in DKO/hA-I mice. Following WD, transcriptomic analysis highlighted in both genotypes an upregulated expression of immune/inflammatory genes and a reduced activation of the retinoid metabolism. The evaluation of the hepatic response of the two genotypes to the dietary switch from SRD to WD revealed strong divergences in genes involved in metabolic pathways only in the presence of apoA-I/HDL, with reduced endogenous sterol biosynthesis and glutathione metabolism, together with increased glucose metabolism. The presence or absence of apoA-I expression differently alters hepatic pathways involved not only in cholesterol metabolism, but also in those of glutathione and glucose metabolism.
2024-10-16 | Apolipoprotein A-I Mimetic Peptide Restores VEGF-induced Angiogenesis in Hypercholesterolemic Ischemic Heart by Reducing HDL Proinflammatory Properties.
VEGF-induced angiogenesis is impaired in hypercholesterolemia. Previous studies showed that an apolipoprotein A-I(ApoA-I) mimetic peptide, D-4F, is able to reduce HDL proinflammatory index in hypercholesterolemia. Whether D-4F promotes angiogenesis in hypercholesterolemia remains unclear. Low-density lipoprotein receptor null (LDLr-/-) mice and LDLr-/-/ApoA-I-/- mice were fed with high-fat diet with or without D-4F (1mg/kg·d). C57BL/6 mice fed with normal diet served as control. The myocardial infarction was induced by ligation coronary artery, and the VEGFA-AAV 9 was injected in heart. The plasma HDL proinflammatory index, cardiac function, infarct size, and angiogenesis related signaling pathways were examined. The HDL proinflammatory index increases in hypercholesterolemic mice. VEGFA stimulates angiogenesis and improves cardiac function in ischemic heart of C57BL/6 mice, but not in hypercholesterolemic mice. D-4F reduces HDL proinflammatory index. D-4F combined with VEGFA stimulates the expression of CD31 and eNOS, activates ERK1/2, reduces infarct size, and improves cardiac function in ischemic heart in hypercholesterolemic LDLr-/- mice but not in hypercholesterolemic LDLr-/-/ApoA-I-/- mice. D-4F restores the VEGF-induced angiogenesis by reducing HDL proinflammatory properties in hypercholesterolemic ischemic heart.
2024-03-19 | Apolipoprotein A-1 Accelerated Liver Regeneration Through Regulating Autophagy Via AMPK-ULK1 Pathway.
Apolipoprotein A-1 (ApoA-1), the main apolipoprotein of high-density lipoprotein, has been well studied in the area of lipid metabolism and cardiovascular diseases. In this project, we clarify the function and mechanism of ApoA-1 in liver regeneration. Seventy percent of partial hepatectomy was applied in male ApoA-1 knockout mice and wild-type mice to investigate the effects of ApoA-1 on liver regeneration. D-4F (ApoA-1 mimetic peptide), autophagy activator, and AMPK activator were used to explore the mechanism of ApoA-1 on liver regeneration. We demonstrated that ApoA-1 levels were highly expressed during the early stage of liver regeneration. ApoA-1 deficiency greatly impaired liver regeneration after hepatectomy. Meanwhile, we found that ApoA-1 deficiency inhibited autophagy during liver regeneration. The activation of autophagy protected against ApoA-1 deficiency in inhibiting liver regeneration. Furthermore, ApoA-1 deficiency impaired autophagy through AMPK-ULK1 pathway, and AMPK activation significantly improved liver regeneration. The administration of D-4F could accelerated liver regeneration after hepatectomy. These findings suggested that ApoA-1 played an essential role in liver regeneration through promoting autophagy in hepatocytes via AMPK-ULK1 pathway. Our findings enrich the understanding of the underlying mechanism of liver regeneration and provide a potential therapeutic strategy for liver injury.
2023-01-03 | Apolipoprotein A-1 protected hepatic ischaemia-reperfusion injury through suppressing macrophage pyroptosis via TLR4-NF-κB pathway.
Apolipoprotein A-1 (ApoA-1), the major apolipoprotein of high-density lipoprotein, plays anti-atherogenic role in cardiovascular diseases and exerts anti-inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA-1 in hepatic ischaemia-reperfusion (I/R) injury is unknown. In this study, we measured ApoA-1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA-1 knockout mice, ApoA-1 mimetic peptide D-4F treatment mice and corresponding control mice to examine the effect of ApoA-1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study. The results showed that ApoA-1 expression was down-regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA-1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA-1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA-1 deficiency. Furthermore, the up-regulated pyroptosis process was testified to be mediated by ApoA-1 through TLR4-NF-κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D-4F ameliorated hepatic I/R injury. Our study has identified the protective role of ApoA-1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4-NF-κB pathway. The effect of ApoA-1 may provide a novel therapeutic approach for hepatic I/R injury.
small molecules
2025-11-22 | Loss of GPR146 decreases plasma levels of HDL cholesterol via post-translational up-regulation of SR-B1 protein levels.
In humans, reduced G-protein coupled receptor 146 (GPR146) expression is associated with reductions in both LDL and HDL cholesterol. While the effects on LDL cholesterol are mediated via the intracellular ERK/SREBP2 pathway, the mechanism explaining how GPR146 affects HDL cholesterol levels remains to be unravelled. Whole-body (Gpr146-/-) and liver-specific Gpr146 knockout (Gpr146 LKO) mice were used to explore changes in HDL metabolism. Wild-type mice were treated with a MEK1 inhibitor to block ERK signalling. HDL uptake and post-translational modification of scavenger receptor class B1 (SR-B1) were studied in murine primary hepatocytes. Genetic variants in GPR146 and SCARB1 served as instruments to examine HDL size and composition in human cohort studies. Investigation in both Gpr146-/- and Gpr146 LKO mice revealed a 20% reduction in HDL cholesterol and a concomitant 30% increase in hepatic SR-B1 protein (without changes in Scarb1 mRNA). This increase was driven by a 2.2-fold increase in cell surface SR-B1 via a mechanism that appears independent of ERK. In vitro studies show that loss of GPR146 increases SR-B1-mediated selective uptake of HDL lipid and HDL protein. Consistently, carriers of a GPR146 variant associated with loss-of-function and carriers of SCARB1 gain-of-function variant share reductions in apoA-I, HDL particle size, HDL cholesterol, and cholesteryl ester content compared to non-carriers. This study suggests that loss of GPR146 reduces HDL cholesterol via post-translational up-regulation of hepatic SR-B1 via an intracellular pathway that remains to be resolved. These findings imply that GPR146 inhibition to treat hypercholesterolaemia may not only lower plasma levels of LDL cholesterol but also HDL cholesterol.
2025-09-01 | Effect of Extra Virgin Olive Oil High in Bioactive Compounds on Atherosclerosis in Apoe-Deficient Mice.
To test the effects of extra virgin olive oil (EVOO) enriched in specific bioactive compounds (EVOO HBC) on atherosclerosis and fatty liver, three isocaloric Western diets differing in the type of fat (palm, EVOO, or EVOO HBC) were fed to Apoe-deficient mice for 12 weeks. Plasma lipids, lipoprotein characterization, circulating CD36-expressing monocytes, and M2 peritoneal macrophages were quantified. Hepatic squalene and cross-sectional and en face atherosclerotic lesions were analyzed. Compared to the palm group, plasma triglyceride and glucose levels increased, while APOA1, paraoxonase 1 activity, and lipoprotein oxidation decreased in mice fed both EVOO groups. The latter stored liver squalene according to the amount consumed. En face and cross-sectional atherosclerotic lesions were lower in the EVOO groups. CD36 expression in circulating monocytes was lower and M2 peritoneal macrophages were higher in the EVOO groups. In males, there was a reduced presence of CD68-expressing cells in atherosclerotic plaques, while in females, there was a reduction in en face lesions that negatively correlated with high-density lipoprotein (HDL)-phospholipid efflux. The recruitment of macrophages into atherosclerotic plaques and the improvement of HDL efflux may be sex-dependent and attributable to the high content of squalene and a specific oleuropein aglycone.
2024-03-06 | Flipped C-Terminal Ends of APOA1 Promote ABCA1-Dependent Cholesterol Efflux by Small HDLs.
Cholesterol efflux capacity (CEC) predicts cardiovascular disease independently of high-density lipoprotein (HDL) cholesterol levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 (ATP-binding cassette transporter A1) pathway, but the underlying mechanisms are unclear. We used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)-deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of APOA1 (apolipoprotein A1) in the different particles, and the CECs of plasma and isolated HDLs. We quantified macrophage and ABCA1 CEC of 4 distinct sizes of reconstituted HDL. CEC increased as particle size decreased. Tandem mass spectrometric analysis of chemically cross-linked peptides and molecular dynamics simulations of APOA1, the major protein of HDL, indicated that the mobility of C-terminus of that protein was markedly higher and flipped off the surface in the smallest particles. To explore the physiological relevance of the model system studies, we isolated HDL from LCAT-deficient subjects, whose small HDLs (like reconstituted HDLs) are discoidal and composed of APOA1, cholesterol, and phospholipid. Despite their very low plasma levels of HDL particles, these subjects had normal CEC. In both the LCAT-deficient subjects and control subjects, the CEC of isolated extra-small HDL (a mixture of extra-small and small HDL by calibrated ion mobility analysis) was 3- to 5-fold greater than that of the larger sizes of isolated HDL. Incubating LCAT-deficient plasma and control plasma with human LCAT converted extra-small and small HDL particles into larger particles, and it markedly inhibited CEC. We present a mechanism for the enhanced CEC of small HDLs. In smaller particles, the C-termini of the 2 antiparallel molecules of APOA1 are "flipped" off the lipid surface of HDL. This extended conformation allows them to engage with ABCA1. In contrast, the C-termini of larger HDLs are unable to interact productively with ABCA1 because they form a helical bundle that strongly adheres to the lipid on the particle. Enhanced CEC, as seen with the smaller particles, predicts decreased cardiovascular disease risk. Thus, extra-small and small HDLs may be key mediators and indicators of the cardioprotective effects of HDL.
2023-12-03 | Functional characterization of missense variants affecting the extracellular domains of ABCA1 using a fluorescence-based assay
Excess cholesterol originating from nonhepatic tissues is transported within HDL particles to the liver for metabolism and excretion. Cholesterol efflux is initiated by lipid-free or lipid-poor apolipoprotein A1 interacting with the transmembrane protein ABCA1, a key player in cholesterol homeostasis. Defective ABCA1 results in reduced serum levels of HDL cholesterol, deposition of cholesterol in arteries, and an increased risk of early onset CVD. Over 300 genetic variants in ABCA1 have been reported, many of which are associated with reduced HDL cholesterol levels. Only a few of these have been functionally characterized. In this study, we have analyzed 51 previously unclassified missense variants affecting the extracellular domains of ABCA1 using a sensitive, easy, and low-cost fluorescence-based assay. Among these, only 12 variants showed a distinct loss-of-function phenotype, asserting their direct association with severe HDL disorders. These findings emphasize the crucial role of functional characterization of genetic variants in pathogenicity assessment and precision medicine. The functional rescue of ABCA1 loss-of-function variants through proteasomal inhibition or by the use of the chemical chaperone 4-phenylbutyric acid was genotype specific. Genotype-specific responses were also observed for the ability of apolipoprotein A1 to stabilize the different ABCA1 variants. In view of personalized medicine, this could potentially form the basis for novel therapeutic strategies.
2023-07-13 | Sulforaphane Inhibits Foam Cell Formation and Atherosclerosis via Mechanisms Involving the Modulation of Macrophage Cholesterol Transport and the Related Phenotype.
Sulforaphane (SFN), an isothiocyanate, is one of the major dietary phytochemicals found in cruciferous vegetables. Many studies suggest that SFN can protect against cancer and cardiometabolic diseases. Despite the proposed systemic and local vascular protective mechanisms, SFN's potential to inhibit atherogenesis by targeting macrophages remains unknown. In this study, in high fat diet fed ApoE-deficient (ApoE-/-) mice, oral SFN treatment improved dyslipidemia and inhibited atherosclerotic plaque formation and the unstable phenotype, as demonstrated by reductions in the lesion areas in both the aortic sinus and whole aorta, percentages of necrotic cores, vascular macrophage infiltration and reactive oxygen species (ROS) generation. In THP-1-derived macrophages, preadministration SFN alleviated oxidized low-density lipoprotein (ox-LDL)-induced lipid accumulation, oxidative stress and mitochondrial injury. Moreover, a functional study revealed that peritoneal macrophages isolated from SFN-treated mice exhibited attenuated cholesterol influx and enhanced apolipoprotein A-I (apoA-I)- and high-density lipoprotein (HDL)-mediated cholesterol efflux. Mechanistic analysis revealed that SFN supplementation induced both intralesional and intraperitoneal macrophage phenotypic switching toward high expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and ATP-binding cassette subfamily A/G member 1 (ABCA1/G1) and low expression of peroxisome proliferator-activated receptor γ (PPARγ) and cluster of differentiation 36 (CD36), which was further validated by the aortic protein expression. These results suggest that the regulation of macrophages' cholesterol transport and accumulation may be mainly responsible for SFN's potential atheroprotective properties, and the regulatory mechanisms might involve upregulating ABCA1/G1 and downregulating CD36 via the modulation of PPARγ and Nrf2.
gene therapies
2025-11-27 | From HDL Deficiency to Neuropathy: Insights into Tangier Disease
Introduction: This review aims to provide a comprehensive examination of Tangier disease, focusing on its clinical manifestations, pathophysiology, and diagnostic methods. The article also delves into the available management strategies, the challenges in treating this rare condition, and the ongoing research into potential therapeutic interventions. Materials and Methods: A comprehensive review of the literature was conducted using the PubMed and Google Scholar databases with the following keywords: "Tangier disease", "HDL deficiency", "ABCA1", "neuropathy", "high-density lipoprotein ", "HDL", "apoA-I", "CETP", "atherosclerosis", "splenomegaly". Summary: Tangier disease is a rare autosomal recessive genetic disorder caused by mutations in the ABCA1 gene, which impairs cholesterol transport and results in low levels of HDL. This leads to the accumulation of cholesterol esters in various tissues, including the tonsils, spleen, lymph nodes, and nerves. The disease is characterized by orange-colored, enlarged tonsils, splenomegaly, peripheral neuropathy, and a heightened risk for atherosclerotic cardiovascular disease. Diagnosis is confirmed through low HDL and apoA-I levels, along with genetic testing for ABCA1 mutations. While no cure exists, treatment focuses on symptom management, controlling cardiovascular risks, and improving HDL function through lifestyle and dietary changes. Conclusions: Tangier disease, a rare genetic disorder caused by mutations in the ABCA1 gene, leads to severe lipid imbalances and various systemic complications. Although there is no cure, managing symptoms, controlling cardiovascular risks, and adopting lifestyle changes are essential for improving outcomes. Ongoing research into gene therapies and new treatments offers hope for future breakthroughs.
2022-06-24 | Lack of ApoA-I in ApoEKO Mice Causes Skin Xanthomas, Worsening of Inflammation, and Increased Coronary Atherosclerosis in the Absence of Hyperlipidemia.
HDL (high-density lipoprotein) and its major protein component, apoA-I (apolipoprotein A-I), play a unique role in cholesterol homeostasis and immunity. ApoA-I deficiency in hyperlipidemic, atheroprone mice was shown to drive cholesterol accumulation and inflammatory cell activation/proliferation. The present study was aimed at investigating the impact of apoA-I deficiency on lipid deposition and local/systemic inflammation in normolipidemic conditions. ApoE deficient mice, apoE/apoA-I double deficient (DKO) mice, DKO mice overexpressing human apoA-I, and C57Bl/6J control mice were fed normal laboratory diet until 30 weeks of age. Plasma lipids were quantified, atherosclerosis development at the aortic sinus and coronary arteries was measured, skin ultrastructure was evaluated by electron microscopy. Blood and lymphoid organs were characterized through histological, immunocytofluorimetric, and whole transcriptome analyses. DKO were characterized by almost complete HDL deficiency and by plasma total cholesterol levels comparable to control mice. Only DKO showed xanthoma formation and severe inflammation in the skin-draining lymph nodes, whose transcriptome analysis revealed a dramatic impairment in energy metabolism and fatty acid oxidation pathways. An increased presence of CD4+ T effector memory cells was detected in blood, spleen, and skin-draining lymph nodes of DKO. A worsening of atherosclerosis at the aortic sinus and coronary arteries was also observed in DKO versus apoE deficient. Human apoA-I overexpression in the DKO background was able to rescue the skin phenotype and halt atherosclerosis development. HDL deficiency, in the absence of hyperlipidemia, is associated with severe alterations of skin morphology, aortic and coronary atherosclerosis, local and systemic inflammation.
2020-02-27 | Hepatic Forkhead Box Protein A3 Regulates ApoA-I (Apolipoprotein A-I) Expression, Cholesterol Efflux, and Atherogenesis.
To determine the role of hepatic FOXA3 (forkhead box A3) in lipid metabolism and atherosclerosis. Approach and Results: Hepatic FOXA3 expression was reduced in diabetic or high fat diet-fed mice or patients with nonalcoholic steatohepatitis. We then used adenoviruses to overexpress or knock down hepatic FOXA3 expression. Overexpression of FOXA3 in the liver increased hepatic ApoA-I (apolipoprotein A-I) expression, plasma HDL-C (high-density lipoprotein cholesterol) level, macrophage cholesterol efflux, and macrophage reverse cholesterol transport. In contrast, knockdown of hepatic FOXA3 expression had opposite effects. We further showed that FOXA3 directly bound to the promoter of the Apoa1 gene to regulate its transcription. Finally, AAV8 (adeno-associated virus serotype 8)-mediated overexpression of human FOXA3 in the hepatocytes of Apoe-/- (apolipoprotein E-deficient) mice raised plasma HDL-C levels and significantly reduced atherosclerotic lesions. Hepatocyte FOXA3 protects against atherosclerosis by inducing ApoA-I and macrophage reverse cholesterol transport.
2019-06-27 | AIBP protects against metabolic abnormalities and atherosclerosis.
Apolipoprotein A-I binding protein (AIBP) has been shown to augment cholesterol efflux from endothelial cells and macrophages. In zebrafish and mice, AIBP-mediated regulation of cholesterol levels in the plasma membrane of endothelial cells controls angiogenesis. The goal of this work was to evaluate metabolic changes and atherosclerosis in AIBP loss-of-function and gain-of-function animal studies. Here, we show that Apoa1bp-/-Ldlr-/- mice fed a high-cholesterol, high-fat diet had exacerbated weight gain, liver steatosis, glucose intolerance, hypercholesterolemia, hypertriglyceridemia, and larger atherosclerotic lesions compared with Ldlr-/- mice. Feeding Apoa1bp-/-Ldlr-/- mice a high-cholesterol, normal-fat diet did not result in significant differences in lipid levels or size of atherosclerotic lesions from Ldlr-/- mice. Conversely, adeno-associated virus-mediated overexpression of AIBP reduced hyperlipidemia and atherosclerosis in high-cholesterol, high-fat diet-fed Ldlr-/- mice. Injections of recombinant AIBP reduced aortic inflammation in Ldlr-/- mice fed a short high-cholesterol, high-fat diet. Conditional overexpression of AIBP in zebrafish also reduced diet-induced vascular lipid accumulation. In experiments with isolated macrophages, AIBP facilitated cholesterol efflux to HDL, reduced lipid rafts content, and inhibited inflammatory responses to lipopolysaccharide.jlr Our data demonstrate that AIBP confers protection against diet-induced metabolic abnormalities and atherosclerosis.
2019-01-07 | HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, PI3K-, and Akt-dependent manner.
Doxorubicin is a widely used chemotherapeutic with deleterious cardiotoxic side effects. HDL has been shown to protect cardiomyocytes in vitro against doxorubicin-induced apoptosis. Scavenger receptor class B type 1 (SR-B1), a high-affinity HDL receptor, mediates cytoprotective signaling by HDL through Akt. Here, we assessed whether increased HDL levels protect against doxorubicin-induced cardiotoxicity in vivo and in cardiomyocytes in culture and explored the intracellular signaling mechanisms involved, particularly the role of SR-B1. Transgenic mice with increased HDL levels through overexpression of human apolipoprotein A1 (apoA1Tg/Tg) and wild-type mice (apoA1+/+) with normal HDL levels were treated repeatedly with doxorubicin. After treatment, apoA1+/+ mice displayed cardiac dysfunction, as evidenced by reduced left ventricular end-systolic pressure and +dP/d t, and histological analysis revealed cardiomyocyte atrophy and increased cardiomyocyte apoptosis after doxorubicin treatment. In contrast, apoA1Tg/Tg mice were protected against doxorubicin-induced cardiac dysfunction and cardiomyocyte atrophy and apoptosis. When SR-B1 was knocked out, however, overexpression of apoA1 did not protect against doxorubicin-induced cardiotoxicity. Using primary neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes in combination with genetic knockout, inhibitors, or siRNA-mediated knockdown, we demonstrated that SR-B1 is required for HDL-mediated protection of cardiomyocytes against doxorubicin-induced apoptosis in vitro via a pathway involving phosphatidylinositol 3-kinase and Akt1/2. Our findings provide proof of concept that raising apoA1 to supraphysiological levels can dramatically protect against doxorubicin-induced cardiotoxicity via a pathway that is mediated by SR-B1 and involves Akt1/2 activation in cardiomyocytes. NEW & NOTEWORTHY We have identified an important role for the scavenger receptor class B type 1 in facilitating high-density lipoprotein-mediated protection of cardiomyocytes against stress-induced apoptosis and shown that increasing plasma high-density lipoprotein protects against the deleterious side effects of the chemotherapeutic and cardiotoxic drug doxorubicin.
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Drug Discovery Landscape
1 orphan drug designation for Apolipoprotein A-I deficiency.
1 orphan drug designation for Apolipoprotein A-I deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Recombinant human apolipoprotein A-I in a complex with phospholipids | proteins | EMA | 2014-08-22 | — | Cerenis Therapeutics Holding SA |
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