Lysyl Oxidase as a Serum Biomarker of Liver Fibrosis in Patients with Severe Obesity and Obstructive Sleep Apnea - PubMed (original) (raw)

. 2015 Oct 1;38(10):1583-91.

doi: 10.5665/sleep.5052.

Mi-Kyung Shin 1, Luciano F Drager 2, Shannon Bevans-Fonti 1, Jonathan C Jun 1, Nirupama Putcha 1, Michael S Torbenson 3, Rodrigo P Pedrosa 4, Geraldo Lorenzi-Filho 4, Kimberley E Steele 5, Michael A Schweitzer 5, Thomas H Magnuson 5, Anne O Lidor 5, Alan R Schwartz 1, Vsevolod Y Polotsky 1

Affiliations

Lysyl Oxidase as a Serum Biomarker of Liver Fibrosis in Patients with Severe Obesity and Obstructive Sleep Apnea

Omar A Mesarwi et al. Sleep. 2015.

Abstract

Study objectives: 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.

Design: 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.

Setting: The Johns Hopkins Bayview Sleep Disorders Center, and the Hypertension Unit of the Heart Institute at the University of São Paulo Medical School.

Measurements and 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.

Keywords: hepatocyte; hypoxia; nonalcoholic fatty liver disease; sleep disordered breathing.

© 2015 Associated Professional Sleep Societies, LLC.

PubMed Disclaimer

Figures

Figure 1

Figure 1

(A) Box plots of apnea-hypoxia index (AHI) in patients with or without hepatic fibrosis. Upper and lower tick marks in each group represent high and low values among each patient cohort; lower and upper bounds on boxes represent first and third quartiles, and midline represents median values. (B) Box plots of serum lysyl oxidase (LOX) in patients with or without histologic evidence of hepatic fibrosis. (C) Receiver operating characteristic (ROC) curve demonstrating the performance of serum LOX. The area under the ROC curve when serum LOX is used as a biomarker of hepatic fibrosis in patients with severe obesity is 0.891 (95% confidence interval, 0.789–0.994). (D) Correlation between AHI and serum LOX levels among all patients studied. R = 0.51, P = 0.002.

Figure 2

Figure 2

(A) Comparison of initial and final serum lysyl oxidase (LOX) values in patients with severe obstructive sleep apnea (OSA) who went untreated (left) and received continuous positive airway pressure (CPAP) therapy (right). Patients who received CPAP had a decline in serum LOX. Mean differences between initial and final values were 20.49 ng/mL (CPAP) and 0.19 ng/mL (control). (B) Correlation between mean nightly CPAP use and decrease in serum LOX among patients with OSA who received CPAP. R = 0.64, P = 0.084.

Figure 3

Figure 3

Hepatic mRNA expression of lysyl oxidase (LOX) in B6129PF2/J mice. Mice were fed a chow diet, exposed either to intermittent hypoxia (IH) or IA for 4 w. LOX is increased 5.2-fold in IH. *P = 0.031 between groups.

Figure 4

Figure 4

Profile of isolated hepatocytes exposed to hypoxia and normoxia. Hepatocytes isolated from C57BL/6 mice express and secrete lysyl oxidase (LOX) in response to hypoxia, resulting in more active collagen cross-linking. (A) Results of reverse-transcriptase polymerase chain reaction demonstrating that expression of LOX messenger RNA from hepatocytes exposed to hypoxia for 24 h is increased (5.9 times normoxia value; *P = 0.046). (B) Results of Western blot showing that LOX is secreted into culture media by hepatocytes exposed to hypoxia for 24 h. (C) Confocal reflection microscopy images of collagen matrices incorporating fixed amounts of concentrated culture media from cells exposed to 16% O2 (left panel), 1% O2 (middle panel), and 1% O2 plus β-aminopropionitrile (BAPN), a LOX inhibitor (right panel). A denser network of precipitated, cross-linked collagen fibers is seen in hypoxia without BAPN. (D) Mean pixel density of collagen from images obtained during the collagen cross-linking experiment in C. P < 0.001 in all group comparisons.

Similar articles

Cited by

References

    1. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The report of an American Academy of Sleep Medicine Task Force. Sleep. 1999;22:667–89. - PubMed
    1. Bonsignore MR, Borel AL, Machan E, Grunstein R. Sleep apnoea and metabolic dysfunction. Eur Respir Rev. 2013;22:353–64. - PMC - PubMed
    1. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–23. - PubMed
    1. Aron-Wisnewsky J, Minville C, Tordjman J, et al. Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese. J Hepatol. 2012;56:225–33. - PubMed
    1. Tanne F, Gagnadoux F, Chazouilleres O, et al. Chronic liver injury during obstructive sleep apnea. Hepatology. 2005;41:1290–6. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources