Adiponectin and the steatosis marker Chi3L1 decrease following switch to raltegravir compared to continued PI/NNRTI-based antiretroviral therapy

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Abstract

Background

People with HIV are at for metabolic syndrome (MetS) and fatty liver disease, but the role of Antiretroviral therapy (ART) is poorly understood. MetS and fatty liver disease been associated with changes in adiponectin, soluble ST2 (sST2), chitinase 3-like 1 (Chi3L1), hyaluronic acid (HA), tissue inhibitor of metalloproteinase-1 (TIMP-1), lysyl oxidase-like-2 (LOXL2) and transforming growth factor β (TGF-β) concentrations in HIV-uninfected populations. Protease (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) may contribute to these comorbidities, but the effects of switching from PI- or NNRTI to raltegravir (RAL) on these biomarkers is unknown.

Methods

Cryopreserved plasma was obtained from a completed, prospective trial of HIV-infected women with central adiposity on NNRTI- or PI-based ART during which they were randomized to remain on their current ART or switch to a RAL based regimen. Biomarker concentrations were quantified using ELISA and Multiplex assays at baseline and 24 weeks after randomization. Wilcoxon-signed rank test evaluated within-group changes, Spearman and linear regression models evaluated correlations between biomarkers and clinical covariates.

Results

Participants had a median age of 43 years, CD4 ⁺ T lymphocyte count 558 cells/mm ³ and BMI 32 kg/m ²; 35% met criteria for MetS. At baseline, higher adiponectin levels correlated with higher Chi3L1 levels (r = 0.42, p = 0.02), as did declines after 24 weeks (r = 0.40, p = 0.03). Changes in sST2 correlated with changes in Chi3L1 (r = 0.43, p = 0.02) and adiponectin (r = 0.40, p = 0.03). Adiponectin and Chi3L1 levels decreased significantly in women switched to RAL vs continue PI/NNRTI.

Conclusion

In women with HIV and central obesity, the hepatic steatosis/fibrosis marker Chi3L1 and adiponectin decrease in conjunction with sST2 decreases following switch to RAL. Whether switching from NNRTI/PI-based regimens to RAL can improve hepatic steatosis and dysmetabolism requires further study.

Trial registration

Clinicaltrials.gov NCT00656175

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Most cited references 42

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The biology of ST2: the International ST2 Consensus Panel.

James Januzzi, Domingo Pascual-Figal (2015)

ST2 is a member of the interleukin 1 receptor family with 2 main isoforms: transmembrane or cellular (ST2L) and soluble or circulating (sST2) forms. ST2 is the receptor of the IL-33, which is an IL-1-like cytokine that can be secreted by living cells in response to cell damage. IL-33 exerts its cellular functions by binding a receptor complex composed of ST2L and IL-1R accessory protein. The IL-33/ST2 system is upregulated in cardiomyocytes and fibroblasts as response to mechanical stimulation or injury. The interaction between IL33 and ST2L has been demonstrated to be cardioprotective: in experimental models, this interaction reduces myocardial fibrosis, prevents cardiomyocyte hypertrophy, reduces apoptosis, and improves myocardial function. The beneficial effects of IL-33 are specifically through the ST2L receptor. sST2 avidly binds IL-33 which results in interruption of the interaction between IL-33/ST2L and consequently eliminates the antiremodeling effects; thus, sST2 is viewed as a decoy receptor. In recent years, knowledge about ST2 role in the pathophysiology of cardiovascular diseases has broadly expanded, with strong links to myocardial dysfunction, fibrosis, and remodeling. Beyond its myocardial role, the IL-33/ST2 system could have an additional role in the development and progression of atherosclerosis. In conclusion, IL-33/ST2L signaling is a mechanically activated, cardioprotective fibroblast-cardiomyocyte paracrine system, which may have therapeutic potential for beneficially regulating the myocardial response to overload and injury. In contrast, sST2 acts as a decoy receptor and, by sequestering IL-33, antagonizes the cardioprotective effects of IL-33/ST2L interaction.

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Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal

Naoki Ikenaga, Zhen-Wei Peng, Kahini Vaid … (2017)

Background/Aims We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice. Methods Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c.Mdr2−/− and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice. Collagen crosslinking, fibrosis progression and reversal were assessed histologically and biochemically. HPC differentiation was studied in primary EpCAM(+) liver cells in vitro. Results LOXL2 was virtually absent from healthy but strongly induced in fibrotic liver, with predominant localisation within fibrotic septa. Delayed anti-LOXL2 treatment of active TAA fibrosis significantly reduced collagen crosslinking and histological signs of bridging fibrosis, with a 53% reduction in morphometric collagen deposition. In established TAA fibrosis, LOXL2 inhibition promoted fibrosis reversal, with enhanced splitting and thinning of fibrotic septa, and a 45% decrease in collagen area at 4 weeks of recovery. In the Mdr2−/− and DDC-induced models of biliary fibrosis, anti-LOXL2 antibody similarly achieved significant antifibrotic efficacy and suppressed the ductular reaction, while hepatocyte replication increased. Blocking LOXL2 had a profound direct effect on primary EpCAM(+) HPC behaviour in vitro, promoting their differentiation towards hepatocytes, while inhibiting ductal cell lineage commitment. Conclusions LOXL2 mediates collagen crosslinking and fibrotic matrix stabilisation during liver fibrosis, and independently promotes fibrogenic HPC differentiation. By blocking these two convergent profibrotic pathways, therapeutic LOXL2 inhibition attenuates both parenchymal and biliary fibrosis and promotes fibrosis reversal.

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Plasma metabolomics identifies lipid abnormalities linked to markers of inflammation, microbial translocation, and hepatic function in HIV patients receiving protease inhibitors

Edana Cassol, Vikas Misra, Alexander Holman … (2013)

Background Metabolic abnormalities are common in HIV-infected individuals on antiretroviral therapy (ART), but the biochemical details and underlying mechanisms of these disorders have not been defined. Methods Untargeted metabolomic profiling of plasma was performed for 32 HIV patients with low nadir CD4 counts (<300 cells/ul) on protease inhibitor (PI)-based ART and 20 healthy controls using liquid or gas chromatography and mass spectrometry. Effects of Hepatitis C (HCV) co-infection and relationships between altered lipid metabolites and markers of inflammation, microbial translocation, and hepatic function were examined. Unsupervised hierarchical clustering, principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), Random forest, pathway mapping, and metabolite set enrichment analysis (MSEA) were performed using dChip, Metaboanalyst, and MSEA software. Results A 35-metabolite signature mapping to lipid, amino acid, and nucleotide metabolism distinguished HIV patients with advanced disease on PI-based ART from controls regardless of HCV serostatus (p<0.05, false discovery rate (FDR)<0.1). Many altered lipids, including bile acids, sulfated steroids, polyunsaturated fatty acids, and eicosanoids, were ligands of nuclear receptors that regulate metabolism and inflammation. Distinct clusters of altered lipids correlated with markers of inflammation (interferon-α and interleukin-6), microbial translocation (lipopolysaccharide (LPS) and LPS-binding protein), and hepatic function (bilirubin) (p<0.05). Lipid alterations showed substantial overlap with those reported in non-alcoholic fatty liver disease (NALFD). Increased bile acids were associated with noninvasive markers of hepatic fibrosis (FIB-4, APRI, and YKL-40) and correlated with acylcarnitines, a marker of mitochondrial dysfunction. Conclusions Lipid alterations in HIV patients receiving PI-based ART are linked to markers of inflammation, microbial translocation, and hepatic function, suggesting that therapeutic strategies attenuating dysregulated innate immune activation and hepatic dysfunction may be beneficial for prevention and treatment of metabolic disorders in HIV patients.

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Author and article information

Contributors

Obiageli Offor:

ORCID: http://orcid.org/0000-0002-0977-5668

Role: Writing – original draftRole: Writing – review & editing

Netanya Utay: Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing

David Reynoso: Role: Data curationRole: Formal analysisRole: Writing – review & editing

Anoma Somasunderam: Role: Data curationRole: Formal analysis

Judith Currier: Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing

Jordan Lake: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Giuseppe Vittorio De Socio: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 10 May 2018

Publication date Collection: 2018

Volume: 13

Issue: 5

Electronic Location Identifier: e0196395

Affiliations

[1 ] Department of Epidemiology, University of Texas Health Science Center Houston, Texas, United States of America

[2 ] Department of Internal Medicine, University of Texas Health Science Center Houston, Texas, United States of America

[3 ] Department of Infectious Disease, University of Texas Medical Branch Galveston, Texas, United States of America

[4 ] Department of Infectious Disease, University of California Los Angeles, California, United States of America

[5 ] Department of Infectious Disease, University of Texas Health Science Center Houston, Texas, United States of America

Azienda Ospedaliera Universitaria di Perugia, ITALY

Author notes

Competing Interests: Judith Currier M.D – Research grant to University of California Los Angeles from Theratechnologies and Merck & Co. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The funders had no role in study design, data collection, analysis, interpretation of data, writing manuscript and the decision to publish. There are no declarations regarding employment, consultancy, patents, products in development or marketed products. There are no non-financial competing interests from any author.

* E-mail: Obiageli.l.offor@ 123456uth.tmc.edu

Author information

Obiageli Offor http://orcid.org/0000-0002-0977-5668

Article

Publisher ID: PONE-D-17-44249

DOI: 10.1371/journal.pone.0196395

PMC ID: 5944924

PubMed ID: 29746485

SO-VID: f07b67e8-c1f6-49ef-bf85-936ae4ffdead

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 4 January 2018

Date accepted : 12 April 2018

Page count

Figures: 5, Tables: 3, Pages: 14