title: Plasma metabolomics identifies lipid abnormalities linked to markers of inflammation, microbial translocation, and hepatic function in HIV patients receiving protease inhibitors.
abstract: 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.
authors: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Edana
authors: E
authors: Cassol
authors: Vikas
authors: V
authors: Misra
authors: Alexander
authors: A
authors: Holman
authors: Anupa
authors: A
authors: Kamat
authors: Susan
authors: S
authors: Morgello
authors: Dana
authors: D
authors: Gabuzda
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000097:blood; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D015331:Cohort Studies; D005234:Fatty Liver / Q000097:blood / Q000378:metabolism* / Q000821:virology; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy* / Q000201:enzymology; D006526:Hepatitis C / Q000201:enzymology / Q000378:metabolism / Q000821:virology; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000378:metabolism*; D016018:Least-Squares Analysis; D052439:Lipid Metabolism Disorders / Q000097:blood / Q000378:metabolism* / Q000821:virology; D008055:Lipids / Q000097:blood; D008297:Male; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D025341:Principal Component Analysis; D011480:Protease Inhibitors / Q000627:therapeutic use
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; D008055:Lipids; D011480:Protease Inhibitors
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