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Albumin in patients with liver disease shows an altered conformation.

ABSTRACT: Human serum albumin (HSA) constitutes the primary transporter of fatty acids, bilirubin, and other plasma compounds. The binding, transport, and release of its cargos strongly depend on albumin conformation, which is affected by bound ligands induced by physiological and pathological conditions. HSA is both highly oxidized and heavily loaded with fatty acids and bilirubin in chronic liver disease. By employing small-angle X-ray scattering we show that HSA from the plasma of chronic liver disease patients undergoes a distinct opening compared to healthy donors. The extent of HSA opening correlates with clinically relevant variables, such as the model of end-stage liver disease score, bilirubin, and fatty acid levels. Although the mild oxidation of HSA in vitro does not alter overall structure, the alteration of patients' HSA correlates with its redox state. This study connects clinical data with structural visualization of albumin dynamicity in solution and underlines the functional importance of albumin's inherent flexibility.

SUBMITTER: Paar M

PROVIDER: S-EPMC8203801 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Albumin in patients with liver disease shows an altered conformation.

Paar Margret M Fengler Vera H VH Rosenberg Daniel J DJ Krebs Angelika A Stauber Rudolf E RE Oettl Karl K Hammel Michal M

Communications biology 20210614 1

Human serum albumin (HSA) constitutes the primary transporter of fatty acids, bilirubin, and other plasma compounds. The binding, transport, and release of its cargos strongly depend on albumin conformation, which is affected by bound ligands induced by physiological and pathological conditions. HSA is both highly oxidized and heavily loaded with fatty acids and bilirubin in chronic liver disease. By employing small-angle X-ray scattering we show that HSA from the plasma of chronic liver disease ...[more]

PMID: 34127764

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Project description:BACKGROUND & AIMS:Patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF) have immune dysfunction, which increases their risk for infections; however, there are no effective treatments to restore their immune function. We investigated whether the potentially immune-restorative effects of albumin are mediated by its effects on prostaglandin E2 (PGE2) and other lipids. METHODS:We analyzed bloods samples from 45 of 79 patients with AD/ACLF and serum levels of albumin less than 30 g/L for whom infusion of 20% human albumin solution (HAS) increased serum levels of albumin 30 g/L or more in a feasibility study of effects of 20% HAS. Immune function was determined by comparison of macrophage function following addition of plasma samples. We also used samples from 12 healthy individuals. We measured binding of plasma proteins to PGE2 and serum levels of endotoxin (lipopolysaccharide) and cytokines; using 10 patients' samples, we investigated the effects of PGE2 inhibitors. We performed a comprehensive lipid metabolomic analysis using samples from 10 different patients, before and after HAS administration. RESULTS:At baseline, AD/ACLF patient plasma induced significantly lower production of tumor necrosis factor by healthy macrophages than plasma from healthy individuals (P < .0001). Plasma from patients after HAS infusion induced significantly higher levels of tumor necrosis factor production by macrophages (19.5 ± 4.8 ng/mL) compared with plasma collected before treatment (17.7 ± 4.5 ng/mL; P = .0013). There was a significantly lower proportion of plasma protein (albumin) binding to PGE2 from patients with AD/ACLF plasma (mean, 61.9%) compared with plasma from control subjects (77.1%; P = .0012). AD/ACLF plasma protein binding to PGE2 increased following HAS treatment compared with baseline (mean increase, 8.7%; P < .0001). Circulating levels of PGE2, lipopolysaccharide, and inflammatory or anti-inflammatory cytokines were higher in patients with AD/ACLF than healthy volunteers. Unexpectedly, HAS infusion had no effect on mediator levels. Principal component analysis of baseline levels of lipids that induce or resolve inflammation identified 2 distinct groups of patients that differed according to baseline plasma level of lipopolysaccharide. Sample analyses after HAS treatment indicated that albumin regulates circulating levels of lipid mediators, but this effect was distinct in each group. CONCLUSIONS:Analysis of blood samples from patients with AD/ACLF participating in a feasibility study of 20% HAS infusions has shown that infusions to raise serum albumin above 30 g/L reversed plasma-mediated immune dysfunction by binding and inactivating PGE2. We also describe a method to classify the inflammatory response in AD/ACLF, based on lipid profile, which could improve identification of patients most likely to respond to HAS treatment. A randomized controlled trial is needed to determine whether these effects of HAS reduce infections in AD/ACLF. Trial registered with European Medicines Agency (EudraCT 2014-002300-24) and adopted by NIHR (ISRCTN14174793).

Project description:Background and aimMaintenance haemodialysis patients have increased morbidity and mortality which is mainly driven by an elevated inflammation level due to the uraemic milieu. A major part of this increased inflammation level is the degree of oxidative stress which can be assessed by albumin redox state (ARS). Aim of this study was to evaluate how the ARS is affected by a haemodialysis treatment and different dialyzer properties.MethodsARS was determined before and after haemodialysis treatment by fractionating it into reduced human mercaptalbumin (HMA), reversibly oxidized human non-mercaptalbumin 1 (HNA-1), and irreversibly oxidized human non-mercaptalbumin 2 (HNA-2) by high-performance liquid chromatography. In healthy individuals, albumin circulates in the following proportions: HMA 70-80%, HNA-1 20-30% and HNA-2 2-5%. High flux (FX 100 [Fresenius Medical Care], BG 1.8 [Toray], Xevonta Hi 18 [B. Braun], CTA-2000 [Kawasumi]) and low flux FX10 [Fresenius Medical Care] dialyzers were used.Results58 patients (59% male, median age 68 years, median time on haemodialysis 32 month) were included in the study. Before haemodialysis treatment, HMA (median 55.9%, IQR 50.1-61.2%) was substantially lower than in healthy individuals. Accordingly, oxidized albumin fractions were above the level of healthy individuals (median HNA-1 38.5%, IQR 33.3-43.2%; median HNA-2 5.8%, IQR 5.1-6.7%). Before haemodialysis treatment HMA was significantly higher in patients usually treated with high flux membranes (p < 0.01). After haemodialysis treatment there was a significant increase of HMA and a decrease of HNA-1 and HNA-2 (p < 0.01). These effects were more pronounced in patients treated with high flux dialyzers (p < 0.01). There were no differences of ARS alteration with regard to the dialyzer´s sterilization mode or the presence of diabetes.ConclusionThe study confirms that the ARS is positively altered by haemodialysis and shows for the first time that this effect depends on dialyzer properties.

Project description:BackgroundAlcohol-associated liver disease (ALD) leads to millions of deaths worldwide annually. A few potential biomarkers of ALD have been discovered through metabolomic or proteomic analysis. Tryptophan (Trp), one of nine essential amino acids, has been extensively studied and shown to play significant roles in many mammalian physiological processes. However, Trp metabolism changes in ALD are not yet fully understood. Whereas urine is an abundant and non-invasive source for disease biomarker discovery the current study investigated whether the abundance of Trp metabolites in the urine of ALD patients differs from that of healthy subjects. We also examined whether, if present in ALD, changes in urinary Trp metabolites can serve as markers for differentiating between mild/moderate and severe ALD.MethodsWe quantified the concentration of Trp and its metabolites in urine samples of healthy controls (n = 18), patients with mild or moderate alcohol-related liver injury (non-severe ALD; n = 21), and patients with severe alcohol-associated hepatitis (severe AH; n = 25) using both untargeted and targeted metabolomics.ResultsEighteen Trp metabolites were identified and quantified from the untargeted metabolomics data. We developed a targeted metabolomics method to quantify the Trp and its metabolites and quantified 17 metabolites from the human urine samples. The data acquired in the untargeted and targeted platforms agreed and showed that the Trp concentration is not affected by the severity of ALD. However, the abundance of 10 Trp metabolites was correlated with the model for end-stage liver disease (MELD) score, with the abundance of nine metabolites significantly different between the healthy control and ALD patient groups.ConclusionWe found that Trp metabolism differs between ALD patients and healthy controls even though the concentration of Trp was not affected. Two Trp metabolites, quinolinic acid and indoxyl sulfate, correlate highly with the severity of ALD.

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Albumin in patients with liver disease shows an altered conformation.

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Albumin in patients with liver disease shows an altered conformation.

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