title: Lysyl Oxidase as a Serum Biomarker of Liver Fibrosis in Patients with Severe Obesity and Obstructive Sleep Apnea.
abstract: OBJECTIVE
  Obstructive sleep apnea (OSA) is associated with the progression of nonalcoholic fatty liver disease (NAFLD). We hypothesized that the hypoxia of OSA increases hepatic production of lysyl oxidase (LOX), an enzyme that cross-links collagen, and that LOX may serve as a biomarker of hepatic fibrosis.
  
  
  METHODS
  Thirty-five patients with severe obesity underwent liver biopsy, polysomnography, and serum LOX testing. A separate group with severe OSA had serum LOX measured before and after 3 mo of CPAP or no therapy, as did age-matched controls. LOX expression and secretion were measured in mouse hepatocytes following exposure to hypoxia.
  
  
  METHODS
  The Johns Hopkins Bayview Sleep Disorders Center, and the Hypertension Unit of the Heart Institute at the University of São Paulo Medical School.
  
  
  RESULTS
  In the bariatric cohort, the apnea-hypopnea index was higher in patients with hepatic fibrosis than in those without fibrosis (42.7 ± 30.2 events/h, versus 16.2 ± 15.5 events/h; P = 0.002), as was serum LOX (84.64 ± 29.71 ng/mL, versus 45.46 ± 17.16 ng/mL; P < 0.001). In the sleep clinic sample, patients with severe OSA had higher baseline LOX than healthy controls (70.75 ng/mL versus 52.36 ng/mL, P = 0.046), and serum LOX decreased in patients with OSA on CPAP (mean decrease 20.49 ng/mL) but not in untreated patients (mean decrease 0.19 ng/mL). Hypoxic mouse hepatocytes demonstrated 5.9-fold increased LOX transcription (P = 0.046), and enhanced LOX protein secretion.
  
  
  CONCLUSIONS
  The hypoxic stress of obstructive sleep apnea may increase circulating lysyl oxidase (LOX) levels. LOX may serve as a biomarker of liver fibrosis in patients with severe obesity and nonalcoholic fatty liver disease.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Mesarwi
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Shin
authors.affiliation: Hypertension Unit, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: Luciano F
authors.initials: LF
authors.lastname: Drager
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Shannon
authors.initials: S
authors.lastname: Bevans-Fonti
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Jun
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Nirupama
authors.initials: N
authors.lastname: Putcha
authors.affiliation: Division of Anatomic Pathology, Mayo Clinic, Rochester, MN.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Torbenson
authors.affiliation: Sleep Laboratory, Pulmonary Division, University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: Rodrigo P
authors.initials: RP
authors.lastname: Pedrosa
authors.affiliation: Sleep Laboratory, Pulmonary Division, University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: Geraldo
authors.initials: G
authors.lastname: Lorenzi-Filho
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Kimberley E
authors.initials: KE
authors.lastname: Steele
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schweitzer
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Magnuson
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Anne O
authors.initials: AO
authors.lastname: Lidor
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Schwartz
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Vsevolod Y
authors.initials: VY
authors.lastname: Polotsky
mesh_terms: D000818:Animals; D050110:Bariatric Surgery; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D015331:Cohort Studies; D003094:Collagen / Q000378:metabolism; D045422:Continuous Positive Airway Pressure; D005260:Female; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000150:complications; D000860:Hypoxia / Q000097:blood / Q000150:complications / Q000201:enzymology; D008103:Liver Cirrhosis / Q000097:blood / Q000150:complications* / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000150:complications / Q000201:enzymology; D009767:Obesity, Morbid / Q000097:blood / Q000150:complications* / Q000201:enzymology*; D017286:Polysomnography; D008249:Protein-Lysine 6-Oxidase / Q000097:blood*; D012890:Sleep; D020181:Sleep Apnea, Obstructive / Q000097:blood / Q000150:complications* / Q000201:enzymology* / Q000628:therapy
chemical_list: D015415:Biomarkers; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase
keywords: hepatocyte; hypoxia; nonalcoholic fatty liver disease; sleep disordered breathing