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Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis.

ABSTRACT: Severe alcoholic hepatitis (SAH) has high mortality. Dysregulated lipid transport and metabolism in liver/macrophages contributes to disease pathophysiology. Paraoxonase/arylesterase 1 (PON1), a liver-specific enzyme, inhibits oxidation of phospholipids and prevents lipid-mediated oxidative damage. However, its functional contribution in macrophage-mediated hepatic injury warrants elucidation. Plasma proteome of patients with SAH (n = 20), alcoholic cirrhosis (n = 20), and healthy controls was analyzed. Dysregulated pathways were identified, validated, and correlated with severity and outcomes in 200 patients with SAH. Tohoku-Hospital-Pediatrics-1 (THP1)-derived macrophages were treated with plasma from study groups in the presence/absence of recombinant PON1 and the phenotype; intracellular lipid bodies and linked functions were evaluated. In patients with SAH, 208 proteins were >1.5 fold differentially regulated (32 up-regulated and 176 down-regulated; P < 0.01).Validation studies confirmed lower levels of lipid transporter proteins (Pon1, apolipoprotein [Apo]B, ApoA1, ApoA2, and ApoC3; P < 0.01). Low PON1 levels inversely correlated with severity and mortality (r2 > 0.3; hazard ratio, 0.91; P < 0.01) and predicted nonsurvivors (area under the receiver operating characteristic curve, 0.86; cut-off, <18 ?g/mL; log rank, <0.01). Low PON1 levels corroborated with increased oxidized low-density lipoprotein levels, intracellular lipid bodies, lipid uptake, lipid metabolism, biosynthesis, and alternative macrophage activation genes in nonsurvivors (P < 0.01). Importantly, in vitro recombinant PON1 treatment on THP1 macrophages reversed these changes (P < 0.01), specifically by alteration in expression of clusters of differentiation 36 (CD36) and adenosine triphosphate-binding cassette subfamily A1 (ABCA1) receptor on macrophages. Conclusion: Lipid transport proteins contribute to the pathogenesis of SAH, and low PON1 levels inversely correlate with the severity of alcoholic hepatitis and 28-day mortality. Restitution of circulating PON1 may be beneficial and needs therapeutic evaluation in patients with SAH.

SUBMITTER: Maras JS

PROVIDER: S-EPMC6887666 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis.

Maras Jaswinder Singh JS Das Sukanta S Bhat Adil A Kumar Vyas Ashish A Yadav Gaurav G Chaudhary Sudrishti S Sukriti Sukriti S Gupta Abhishak C AC Bihari Chagan C Mahiwall Rakhi R Sarin Shiv Kumar SK

Hepatology communications 20191030 12

Severe alcoholic hepatitis (SAH) has high mortality. Dysregulated lipid transport and metabolism in liver/macrophages contributes to disease pathophysiology. Paraoxonase/arylesterase 1 (PON1), a liver-specific enzyme, inhibits oxidation of phospholipids and prevents lipid-mediated oxidative damage. However, its functional contribution in macrophage-mediated hepatic injury warrants elucidation. Plasma proteome of patients with SAH (n = 20), alcoholic cirrhosis (n = 20), and healthy controls was a ...[more]

PMID: 31832570

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Project description:Alcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. The immune system in patients with AH is hyperactive and yet dysfunctional. Here, we investigated whether this immune-dysregulated state is related to the alcoholic impact on immune checkpoints (ICPs). We used multiplex immunoassays and enzyme-linked immunosorbent assay to quantify plasma levels of 18 soluble ICPs (sICPs) from 81 patients with AH, 65 heavy drinkers without liver diseases (HDCs), and 39 healthy controls (HCs) at baseline, 33 patients with AH and 32 HDCs at 6-month follow-up, and 18 patients with AH and 29 HDCs at 12-month follow-up. We demonstrated that baseline levels of 6 sICPs (soluble T-cell immunoglobulin and mucin domain 3 [sTIM-3], soluble cluster of differentiation [sCD]27, sCD40, soluble Toll-like receptor-2 [sTLR-2], soluble herpesvirus entry mediator [sHVEM], and soluble lymphotoxin-like inducible protein that competes with glycoprotein D for herpes virus entry on T cells [sLIGHT]) were up-regulated, while 11 sICPs (soluble B- and T-lymphocyte attenuator [sBTLA], sCD160, soluble cytotoxic T-lymphocyte-associated protein 4 [sCTLA-4], soluble lymphocyte-activation gene 3 [sLAG-3], soluble programmed death 1 [sPD-1], sPD ligand 1 [sPD-L1], sCD28, soluble glucocorticoid-induced tumor necrosis factor receptor-related protein [sGITR], sGITR ligand [sGITRL], sCD80, and inducible T-cell costimulator [sICOS]) were down-regulated in patients with AH compared to HDCs. The up-regulated sICPs except sLIGHT and down-regulated sCD80, sCD160, sCTLA-4, and sLAG-3 correlated positively or negatively with AH disease severity, bacterial translocation, and inflammatory factors. At follow-up, abstinent patients with AH still had higher levels of several sICPs compared to HDCs. We also compared expression of 10 membrane-bound ICPs (mICPs) on peripheral blood mononuclear cells (PBMCs) from patients with AH and HCs by flow cytometry and found that several mICPs were dysregulated on blood cells from patients with AH. The function and regulation of sICPs and mICPs were studied using PBMCs from patients with AH and HCs. Recombinant sHVEM affected tumor necrosis factor (TNF)-α and interferon-γ production by T cells from patients with AH and HCs. Conclusion: Both sICPs and mICPs were dysregulated in patients with AH, and alcohol abstinence did not fully reverse these abnormalities. The HVEM axis plays a role in regulating T-cell function in patients with AH.

Project description:Severe alcoholic hepatitis (SAH) has a high mortality rate, and corticosteroid therapy is effective in 60% patients. This study aimed to investigate a baseline metabolic phenotype that could help stratify patients not likely to respond to steroid therapy and to have an unfavorable outcome. Baseline urine metabolome was studied in patients with SAH using ultra-high performance liquid chromatography and high-resolution mass spectrometry. Patients were categorized as responders (Rs, n = 52) and nonresponders (NRs, n = 8) at day 7 according to the Lille score. Multivariate projection analysis identified metabolites in the discovery cohort (n = 60) and assessed these in a validation cohort of 80 patients (60 Rs, 20 NRs). A total of 212 features were annotated by using metabolomic/biochemical/spectral databases for metabolite identification. After a stringent selection procedure, a total of nine urinary metabolites linked to mitochondrial functions significantly discriminated nonresponders, most importantly by increased acetyl-L-carnitine (12-fold), octanoylcarnitine (4-fold), decanoylcarnitine (4-fold), and alpha-ketoglutaric acid (2-fold) levels. Additionally, urinary acetyl-L-carnitine and 3-hydroxysebasic acid discriminated nonsurvivors (P < 0.01). These urinary metabolites significantly correlated to severity indices and mortality (r > 0.3; P < 0.01) and were associated with nonresponse (odds ratio >3.0; P < 0.001). In the validation cohort, baseline urinary acetyl-L-carnitine documented an area under the receiver operating curve of 0.96 (0.85-0.99) for nonresponse prediction and a hazard ratio of 3.5 (1.5-8.3) for the prediction of mortality in patients with SAH. Acetyl-L-carnitine at a level of >2,500 ng/mL reliably segregated survivors from nonsurvivors (P < 0.01, log-rank test) in our study cohort. Conclusion: Urinary metabolome signatures related to mitochondrial functions can predict pretherapy steroid response and disease outcome in patients with SAH. (Hepatology Communications 2018;2:628-643).

Project description:Background and objectivesWhile animal studies have implicated derangements of global energy homeostasis in the pathogenesis of acute alcoholic hepatitis (AAH), the relevance of these findings to the development of human AAH remains unclear. Using global, unbiased serum metabolomics analysis, we sought to characterize alterations in metabolic pathways associated with severe AAH and identify potential biomarkers for disease prognosis.MethodsThis prospective, case-control study design included 25 patients with severe AAH and 25 ambulatory patients with alcoholic cirrhosis. Serum samples were collected within 24 hours of the index clinical encounter. Global, unbiased metabolomics profiling was performed. Patients were followed for 180 days after enrollment to determine survival.ResultsLevels of 234 biochemicals were altered in subjects with severe AAH. Random-forest analysis, principal component analysis, and integrated hierarchical clustering methods demonstrated that metabolomics profiles separated the two cohorts with 100% accuracy. Severe AAH was associated with enhanced triglyceride lipolysis, impaired mitochondrial fatty acid beta oxidation, and upregulated omega oxidation. Low levels of multiple lysolipids and related metabolites suggested decreased plasma membrane remodeling in severe AAH. While most measured bile acids were increased in severe AAH, low deoxycholate and glycodeoxycholate levels indicated intestinal dysbiosis. Several changes in substrate utilization for energy homeostasis were identified in severe AAH, including increased glucose consumption by the pentose phosphate pathway, altered tricarboxylic acid (TCA) cycle activity, and enhanced peptide catabolism. Finally, altered levels of small molecules related to glutathione metabolism and antioxidant vitamin depletion were observed in patients with severe AAH. Univariable logistic regression revealed 15 metabolites associated with 180-day survival in severe AAH.ConclusionSevere AAH is characterized by a distinct metabolic phenotype spanning multiple pathways. Metabolomics profiling revealed a panel of biomarkers for disease prognosis, and future studies are planned to validate these findings in larger cohorts of patients with severe AAH.

Dataset Information

Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis.

Publications

Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis.

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