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Arteriosclerosis, Thrombosis, and... Mar 2022Elevated plasma Lp(a) (lipoprotein(a)) levels are associated with increased risk for atherosclerotic cardiovascular disease and aortic valve stenosis. However, the cell...
BACKGROUND
Elevated plasma Lp(a) (lipoprotein(a)) levels are associated with increased risk for atherosclerotic cardiovascular disease and aortic valve stenosis. However, the cell biology of Lp(a) biosynthesis remains poorly understood, with the locations of the noncovalent and covalent steps of Lp(a) assembly unclear and the nature of the apoB-containing particle destined for Lp(a) unknown. We, therefore, asked if apo(a) and apoB interact noncovalently within hepatocytes and if this impacts Lp(a) biosynthesis.
METHODS
Using human hepatocellular carcinoma cells expressing 17K (17 kringle) apo(a), or a 17KΔLBS7,8 variant with a reduced ability to bind noncovalently to apoB, we performed coimmunoprecipitation, coimmunofluorescence, and proximity ligation assays to document intracellular apo(a):apoB interactions. We used a pulse-chase metabolic labeling approach to measure apo(a) and apoB secretion rates.
RESULTS
Noncovalent complexes containing apo(a)/apoB are present in lysates from cells expressing 17K but not 17KΔLBS7,8, whereas covalent apo(a)/apoB complexes are absent from lysates. 17K and apoB colocalized intracellularly, overlapping with staining for markers of endoplasmic reticulum trans-Golgi, and early endosomes, and less so with lysosomes. The 17KΔLBS7,8 had lower colocalization with apoB. Proximity ligation assays directly documented intracellular 17K/apoB interactions, which were dramatically reduced for 17KΔLBS7,8. Treatment of cells with PCSK9 (proprotein convertase subtilisin/kexin type 9) enhanced, and lomitapide reduced, apo(a) secretion in a manner dependent on the noncovalent interaction between apo(a) and apoB. Apo(a) secretion was also reduced by siRNA-mediated knockdown of .
CONCLUSIONS
Our findings explain the coupling of apo(a) and Lp(a)-apoB production observed in human metabolic studies using stable isotopes as well as the ability of agents that inhibit apoB biosynthesis to lower Lp(a) levels.
Topics: Apolipoprotein B-100; Apolipoproteins A; Binding Sites; Hep G2 Cells; Hepatocytes; Humans; Kringles; Lipoprotein(a); Lysine; Metabolic Networks and Pathways; Multiprotein Complexes; Protein Binding; Recombinant Proteins
PubMed: 35045727
DOI: 10.1161/ATVBAHA.121.317335 -
Pharmacological Research Aug 2020Angiogenesis is a finely co-ordinated, multi-step developmental process of the new vascular structure. Even though angiogenesis is regularly occurring in physiological... (Review)
Review
Angiogenesis is a finely co-ordinated, multi-step developmental process of the new vascular structure. Even though angiogenesis is regularly occurring in physiological events such as embryogenesis, in adults, it is restricted to specific tissue sites where rapid cell-turnover and membrane synthesis occurs. Both excessive and insufficient angiogenesis lead to vascular disorders such as cancer, ocular diseases, diabetic retinopathy, atherosclerosis, intra-uterine growth restriction, ischemic heart disease, stroke etc. Occurrence of altered lipid profile and vascular lipid deposition along with vascular disorders is a hallmark of impaired angiogenesis. Among lipoproteins, lipoprotein(a) needs special attention due to the presence of a multi-kringle protein subunit, apolipoprotein(a) [apo(a)], which is structurally homologous to many naturally occurring anti-angiogenic proteins such as plasminogen and angiostatin. Researchers have constructed different recombinant forms of apo(a) (rhLK68, rhLK8, RHACK2, KV-11, and AU-6) and successfully exploited its potential to inhibit unwanted angiogenesis during tumor metastasis and retinal neovascularization. Similar to naturally occurring anti-angiogenic proteins, apo(a) can directly interfere with angiogenic signaling pathways. Besides this, apo(a) can also exert its anti-angiogenic effect indirectly by inducing endothelial cell apoptosis, by inhibiting endothelial progenitor cell functions or by upregulating nuclear factors in endothelial cells via apo(a)-bound oxPLs. However, the impact of the anti-angiogenic potential of native apo(a) during physiological angiogenesis in embryos and wounded tissues is not yet explored. In this context, we review the studies so far done to demonstrate the anti-angiogenic activity of apo(a) and the recent developments in using apo(a) as a therapeutic agent to treat impaired angiogenesis during vascular disorders, with emphasis on the gaps in the literature.
Topics: Angiogenesis Inhibitors; Animals; Apolipoproteins A; Humans; Neovascularization, Pathologic; Neovascularization, Physiologic
PubMed: 32430285
DOI: 10.1016/j.phrs.2020.104858 -
Endocrinology and Metabolism Clinics of... Dec 2014This article reconciles the classic view of high-density lipoproteins (HDL) associated with low risk for cardiovascular disease (CVD) with recent data (genetics studies... (Review)
Review
This article reconciles the classic view of high-density lipoproteins (HDL) associated with low risk for cardiovascular disease (CVD) with recent data (genetics studies and randomized clinical trials) casting doubt over the widely accepted beneficial role of HDL regarding CVD risk. Although HDL cholesterol has been used as a surrogate measure to investigate HDL function, the cholesterol content in HDL particles is not an indicator of the atheroprotective properties of HDL. Thus, more precise measures of HDL metabolism are needed to reflect and account for the beneficial effects of HDL particles. Current and emerging therapies targeting HDL are discussed.
Topics: Apolipoprotein A-I; Biomarkers; Cardiovascular Diseases; Humans; Lipoproteins, HDL; Metabolic Networks and Pathways
PubMed: 25432389
DOI: 10.1016/j.ecl.2014.08.001 -
Journal of Lipid Research Aug 2015The purpose of this review is to summarize our current understanding of the physiological roles of apoA-IV in metabolism, and to underscore the potential for apoA-IV to... (Review)
Review
The purpose of this review is to summarize our current understanding of the physiological roles of apoA-IV in metabolism, and to underscore the potential for apoA-IV to be a focus for new therapies aimed at the treatment of diabetes and obesity-related disorders. ApoA-IV is primarily synthesized by the small intestine, attached to chylomicrons by enterocytes, and secreted into intestinal lymph during fat absorption. In circulation, apoA-IV is associated with HDL and chylomicron remnants, but a large portion is lipoprotein free. Due to its anti-oxidative and anti-inflammatory properties, and because it can mediate reverse-cholesterol transport, proposed functions of circulating apoA-IV have been related to protection from cardiovascular disease. This review, however, focuses primarily on several properties of apoA-IV that impact other metabolic functions related to food intake, obesity, and diabetes. In addition to participating in triglyceride absorption, apoA-IV can act as an acute satiation factor through both peripheral and central routes of action. It also modulates glucose homeostasis through incretin-like effects on insulin secretion, and by moderating hepatic glucose production. While apoA-IV receptors remain to be conclusively identified, the latter modes of action suggest that this protein holds therapeutic promise for treating metabolic disease.
Topics: Animals; Apolipoproteins A; Bariatric Surgery; Gene Expression Regulation; Humans; Metabolism
PubMed: 25640749
DOI: 10.1194/jlr.R052753 -
BMC Medicine Nov 2023Sepsis is characterized by a dysregulated immune response and metabolic alterations, including decreased high-density lipoprotein cholesterol (HDL-C) levels. HDL...
BACKGROUND
Sepsis is characterized by a dysregulated immune response and metabolic alterations, including decreased high-density lipoprotein cholesterol (HDL-C) levels. HDL exhibits beneficial properties, such as lipopolysaccharides (LPS) scavenging, exerting anti-inflammatory effects and providing endothelial protection. We investigated the effects of CER-001, an engineered HDL-mimetic, in a swine model of LPS-induced acute kidney injury (AKI) and a Phase 2a clinical trial, aiming to better understand its molecular basis in systemic inflammation and renal function.
METHODS
We carried out a translational approach to study the effects of HDL administration on sepsis. Sterile systemic inflammation was induced in pigs by LPS infusion. Animals were randomized into LPS (n = 6), CER20 (single dose of CER-001 20 mg/kg; n = 6), and CER20 × 2 (two doses of CER-001 20 mg/kg; n = 6) groups. Survival rate, endothelial dysfunction biomarkers, pro-inflammatory mediators, LPS, and apolipoprotein A-I (ApoA-I) levels were assessed. Renal and liver histology and biochemistry were analyzed. Subsequently, we performed an open-label, randomized, dose-ranging (Phase 2a) study included 20 patients with sepsis due to intra-abdominal infection or urosepsis, randomized into Group A (conventional treatment, n = 5), Group B (CER-001 5 mg/kg BID, n = 5), Group C (CER-001 10 mg/kg BID, n = 5), and Group D (CER-001 20 mg/kg BID, n = 5). Primary outcomes were safety and efficacy in preventing AKI onset and severity; secondary outcomes include changes in inflammatory and endothelial dysfunction markers.
RESULTS
CER-001 increased median survival, reduced inflammatory mediators, complement activation, and endothelial dysfunction in endotoxemic pigs. It enhanced LPS elimination through the bile and preserved liver and renal parenchyma. In the clinical study, CER-001 was well-tolerated with no serious adverse events related to study treatment. Rapid ApoA-I normalization was associated with enhanced LPS removal and immunomodulation with improvement of clinical outcomes, independently of the type and gravity of the sepsis. CER-001-treated patients had reduced risk for the onset and progression to severe AKI (stage 2 or 3) and, in a subset of critically ill patients, a reduced need for organ support and shorter ICU length of stay.
CONCLUSIONS
CER-001 shows promise as a therapeutic strategy for sepsis management, improving outcomes and mitigating inflammation and organ damage.
TRIAL REGISTRATION
The study was approved by the Agenzia Italiana del Farmaco (AIFA) and by the Local Ethic Committee (N° EUDRACT 2020-004202-60, Protocol CER-001- SEP_AKI_01) and was added to the EU Clinical Trials Register on January 13, 2021.
Topics: Humans; Animals; Swine; Lipoproteins, HDL; Apolipoprotein A-I; Lipopolysaccharides; Translational Research, Biomedical; Inflammation; Sepsis; Acute Kidney Injury; Inflammation Mediators
PubMed: 37915050
DOI: 10.1186/s12916-023-03057-5 -
Biochimica Et Biophysica Acta.... Sep 2022The discovery of apolipoprotein A5 (APOA5) in 2001 has raised a number of intriguing questions about its role in lipid transport and triglyceride (TG) homeostasis.... (Review)
Review
The discovery of apolipoprotein A5 (APOA5) in 2001 has raised a number of intriguing questions about its role in lipid transport and triglyceride (TG) homeostasis. Genome-wide association studies have consistently identified APOA5 as a regulator of plasma TG levels, which is further supported by studies in transgenic and knockout mouse models. The present review describes recent concepts pertaining to the roles of APOA5 in TG metabolism as related to the vascular compartment, liver, adipose tissue and the gut. Recent evidence indicates that APOA5 may also affect postprandial TG metabolism through influencing chylomicron formation and transport by the intestine into the intestinal lymph. While substantial evidence supports the notion that APOA5 plays both extracellular and intracellular roles in TG homeostasis, mysteries remain on how this low-abundance, liver-derived protein may modulate TG homeostasis, including via the gut. Given the strong correlation between elevated plasma TG and cardiometabolic diseases, there is great scientific and public interest in understanding the intriguing mysteries presented by APOA5.
Topics: Animals; Apolipoprotein A-V; Fasting; Humans; Mice; Triglycerides
PubMed: 35644522
DOI: 10.1016/j.bbalip.2022.159185 -
Canadian Journal of Diabetes Jul 2020Our aim in this study was to assess the relationship between serum lipoprotein(a) [Lp(a)] and apolipoproteins and the risk of developing diabetic retinopathy (DR).
OBJECTIVES
Our aim in this study was to assess the relationship between serum lipoprotein(a) [Lp(a)] and apolipoproteins and the risk of developing diabetic retinopathy (DR).
METHODS
One thousand fifty-seven patients with type 2 diabetes were divided into 2 main groups and followed for 5 years: 637 patients without DR and 420 patients with DR. A group of patients with DR were then divided into 2 subgroups: 162 patients with nonproliferative DR (NPDR) and 163 patients with proliferative DR (PDR). The association between serum Lp(a) and apolipoproteins with NPDR and PDR was assessed using univariate and multivariate regression analyses. Receiver-operating characteristic curve analysis was performed based on the new cutoff values.
RESULTS
There was a positive relationship between Lp(a) and the presence of DR as well as a negative correlation between ApoA and DR (p<0.001 and p=0.03, respectively). We also found a positive association between ApoB and the severity of DR (p=0.008). ApoA1 had an area under the curve of 55.0% for the prediction of DR. The calculated cutoff values of ApoB/ApoA1 ratio (0.58 g/L) and ApoB (77.5 g/L) in detection of DR were lower than their standard cutoff values of 0.8 and 90 g/L, respectively. Also, the sensitivity of new cutoff values for ApoB and ApoB/ApoA1 ratio was higher than the standard value, but the specificity of the standard cutoff values for both was higher than our new cutoff value.
CONCLUSIONS
Serum Lp(a) and ApoA1 levels were independently associated with DR, and serum ApoB correlated with severity of DR. These measurements can be used for assessment and early treatment of this vision-threatening complication of diabetes.
Topics: Adult; Aged; Apolipoprotein A-I; Apolipoproteins A; Apolipoproteins B; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Lipoprotein(a); Male; Middle Aged; ROC Curve
PubMed: 32205075
DOI: 10.1016/j.jcjd.2020.01.007 -
Journal of Lipid Research Mar 2023Lipoprotein(a) [Lp(a)] has two main proteins, apoB100 and apo(a). High levels of Lp(a) confer an increased risk for atherosclerotic cardiovascular disease. Most people...
Lipoprotein(a) [Lp(a)] has two main proteins, apoB100 and apo(a). High levels of Lp(a) confer an increased risk for atherosclerotic cardiovascular disease. Most people have two circulating isoforms of apo(a) differing in their molecular mass, determined by the number of Kringle IV Type 2 repeats. Previous studies report a strong inverse relationship between Lp(a) levels and apo(a) isoform sizes. The roles of Lp(a) production and fractional clearance and how ancestry affects this relationship remain incompletely defined. We therefore examined the relationships of apo(a) size with Lp(a) levels and both apo(a) fractional clearance rates (FCR) and production rates (PR) in 32 individuals not on lipid-lowering treatment. We determined plasma Lp(a) levels and apo(a) isoform sizes, and used the relative expression of the two isoforms to calculate a "weighted isoform size" (wIS). Stable isotope studies were performed, using D3-leucine, to determine the apo(a) FCR and PR. As expected, plasma Lp(a) concentrations were inversely correlated with wIS (R = 0.27; P = 0.002). The wIS had a modest positive correlation with apo(a) FCR (R = 0.10, P = 0.08), and a negative correlation with apo(a) PR (R = 0.11; P = 0.06). The relationship between wIS and PR became significant when we controlled for self-reported race and ethnicity (SRRE) (R = 0.24, P = 0.03); controlling for SRRE did not affect the relationship between wIS and FCR. Apo(a) wIS plays a role in both FCR and PR; however, adjusting for SRRE strengthens the correlation between wIS and PR, suggesting an effect of ancestry.
Topics: Humans; Lipoprotein(a); Apoprotein(a); Apolipoproteins A; Atherosclerosis; Protein Isoforms
PubMed: 36706955
DOI: 10.1016/j.jlr.2023.100336 -
Clinical Chemistry Feb 2019
Topics: Apolipoprotein A-I; Cholesterol; Coronary Artery Disease; Humans; Lipoproteins; Mass Spectrometry; Proteome
PubMed: 30523200
DOI: 10.1373/clinchem.2018.298869 -
Journal of Internal Medicine May 2022Chronic kidney disease (CKD) represents a chronic proinflammatory state and is associated with very high cardiovascular risk. Apolipoprotein A-IV (apoA-IV) has...
BACKGROUND
Chronic kidney disease (CKD) represents a chronic proinflammatory state and is associated with very high cardiovascular risk. Apolipoprotein A-IV (apoA-IV) has antiatherogenic, antioxidative, anti-inflammatory and antithrombotic properties and levels increase significantly during the course of CKD.
OBJECTIVES
We aimed to investigate the association between apoA-IV and all-cause mortality and cardiovascular outcomes in the German Chronic Kidney Disease study.
METHODS
This was a prospective cohort study including 5141 Caucasian patients with available apoA-IV measurements and CKD. The majority of the patients had an estimated glomerular filtration rate (eGFR) of 30-60 ml/min/1.73m or an eGFR >60 ml/min/1.73m in the presence of overt proteinuria. Median follow-up was 6.5 years. The association of apoA-IV with comorbidities at baseline and endpoints during follow-up was modelled adjusting for major confounders.
RESULTS
Mean apoA-IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dl. Patients in the highest apoA-IV quartile had the lowest high-sensitivity C-reactive protein values despite the highest prevalence of diabetes, albuminuria and the lowest eGFR. Each 10 mg/dl higher apoA-IV translated into lower odds of prevalent cardiovascular disease (1289 cases, odds ratio = 0.80, 95% confidence interval [CI] 0.72-0.86, p = 0.0000003). During follow-up, each 10 mg/dl higher apoA-IV was significantly associated with a lower risk for all-cause mortality (600 cases, hazard ratio [HR] = 0.81, 95% CI 0.73-0.89, p = 0.00004), incident major adverse cardiovascular events (506 cases, HR = 0.88, 95% CI 0.79-0.99, p = 0.03) and death or hospitalizations due to heart failure (346 cases, HR = 0.84, 95% CI 0.73-0.96, p = 0.01).
CONCLUSIONS
These data support a link between elevated apoA-IV concentrations and reduced inflammation in moderate CKD. ApoA-IV appears to be an independent risk marker for reduced all-cause mortality, cardiovascular events and heart failure in a large cohort of patients with CKD.
Topics: Apolipoproteins A; Cardiovascular Diseases; Glomerular Filtration Rate; Heart Failure; Humans; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors
PubMed: 34914850
DOI: 10.1111/joim.13437