Advertisement

Digestive Diseases and Sciences

, Volume 64, Issue 7, pp 1878–1892 | Cite as

Serum and Fecal Oxylipins in Patients with Alcohol-Related Liver Disease

  • Bei Gao
  • Sonja Lang
  • Yi Duan
  • Yanhan Wang
  • Debbie L. Shawcross
  • Alexandre Louvet
  • Philippe Mathurin
  • Samuel B. Ho
  • Peter Stärkel
  • Bernd SchnablEmail author
Original Article

Abstract

Background

Alcohol-related liver disease is one of the most prevalent chronic liver diseases worldwide. Mechanisms involved in the pathogenesis of alcohol-related liver disease are not well understood. Oxylipins play a crucial role in numerous biological processes and pathological conditions. Nevertheless, oxylipins are not well studied in alcohol-related liver disease.

Aims

(1) To characterize the patterns of bioactive ω-3 and ω-6 polyunsaturated fatty acid metabolites in alcohol use disorder and alcoholic hepatitis patients and (2) to identify associations of serum oxylipins with clinical parameters in patients with alcohol-related liver disease.

Methods

We performed a comprehensive liquid chromatography with tandem mass spectrometry (LC–MS/MS) analysis of serum and fecal oxylipins derived from ω-6 arachidonic acid, ω-3 eicosapentaenoic acid, and docosahexaenoic acid in a patient cohort with alcohol-related liver disease.

Results

Our results show profound alterations in the serum oxylipin profile of patients with alcohol use disorder and alcoholic hepatitis compared to nonalcoholic controls. Spearman correlation of the oxylipins with clinical parameters shows a link between different serum oxylipins and intestinal permeability, aspartate aminotransferase, bilirubin, albumin, international normalized ratio, platelet count, steatosis, fibrosis and model for end-stage liver disease score. Especially, higher level of serum 20-HETE was significantly associated with decreased albumin, increased hepatic steatosis, polymorphonuclear infiltration, and 90-day mortality.

Conclusions

Patients with alcohol-related liver disease have different oxylipin profiles. Future studies are required to confirm oxylipins as disease biomarker or to connect oxylipins to disease pathogenesis.

Keywords

AA EPA DHA PUFA Lipid mediator Metabolomics 

Abbreviations

AP

Alkaline phosphatase

AST

Aspartate aminotransferase

ALT

Alanine aminotransferase

BMI

Body mass index

CAP

Controlled attenuation parameter

INR

International normalized ratio

MELD

Model for end-stage liver disease

MELDNa

Sodium model for end-stage liver disease

PMN

Polymorphonuclear infiltration

AA

Arachidonic acid

EPA

Eicosapentaenoic acid

DHA

Docosahexaenoic acid

HpETE

Hydroperoxyeicosatetraenoic acid

HETE

Hydroxyeicosatetraenoic acid

DiHETE

Dihydroxyeicosatetraenoic acid

PG

Prostaglandin

TX

Thromboxane X

EpETrE

Epoxyeicosatrienoic acid

DiHETrE

Dihydroxyeicosatrienoic acid

HpEPE

Hydroperoxy-eicosapentaenoic acid

HEPE

Hydroxyeicosapentaenoic acid

DiHEPE

Dihydroxyeicosapentaenoic acid

EpETE

Epoxyeicosatetraenoic acid

HpDoHE

Hydroperoxydocosahexaenoic acid

HDoHE

Hydroxydocosahexaenoic acid

DiHDoHE

Dihydroxydocosahexaenoic acid

DiHDPE

Dihydroxydocosapentaenoic acid

PLS-DA

Partial least squares discriminant analysis

VIP

Variable importance in projection

MRM

Multiple reaction monitoring

Notes

Acknowledgments

This study was supported in part by NIH Grants R01 AA020703, R01 AA24726, U01 AA021856, U01 AA026939 and by Award Number BX004594 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (to B.S.), and by Fond National de Recherche Scientifique (FNRS) Belgium grants CDR J.0146.17 and PDR T.0217.18 (to P.S.).

Author’s Contribution

B.G. was responsible for data acquisition, analysis, interpretation, and writing of the manuscript; S.L. was responsible for data analysis; Y.D. and Y.W. were responsible for preparation of human samples; D.L.S., A.L., P.M., S.B.H., and P.S. enrolled subjects for bio-specimen collection; and B.S. was responsible for the study concept and design, editing the manuscript, and study supervision.

Compliance with Ethical Standards

Conflict of interest

B.S. is consulting for Ferring Research Institute.

Supplementary material

10620_2019_5638_MOESM1_ESM.jpg (165 kb)
Supplemental Figure S1 Venn diagram of significantly altered oxylipins found in both serum and fecal samples (adjusted p value < 0.05). Ctrl: controls; AUD: alcoholic use disorder; AH: alcoholic hepatitis (JPEG 165 kb)
10620_2019_5638_MOESM2_ESM.jpg (268 kb)
Supplemental Figure S2 Spearman correlation of fecal oxylipins with laboratory parameters in alcoholic hepatitis and alcohol use disorder patients. Color intensity represents the correlation coefficient (R). Red: positive correlation. Blue: negative correlation. * p < 0.05, ** p < 0.01, *** p < 0.001. INR, international normalized ratio; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; AP, alkaline phosphatase (JPEG 267 kb)
10620_2019_5638_MOESM3_ESM.jpg (487 kb)
Supplemental Figure S3 Spearman correlation of fecal oxylipins with parameters of liver disease stage in alcohol use disorder patients (A). CAP: controlled attenuation parameter. Color intensity represents the correlation coefficient (R). Red: positive correlation. Blue: negative correlation. * p < 0.05. Number of alcohol use disorder patients N = 30. Spearman correlation of fecal oxylipins with liver histology and clinical scores in alcoholic hepatitis patients (B). Color intensity represents the correlation coefficient (R). Red: positive correlation. Blue: negative correlation. * p < 0.05, ** p < 0.01, *** p < 0.001. MELD, model for end-stage liver disease; MELDNa, sodium model for end-stage liver disease. Number of alcoholic hepatitis patients N = 7 (JPEG 486 kb)
10620_2019_5638_MOESM4_ESM.xlsx (17 kb)
Supplementary material 4 (XLSX 17 kb)
10620_2019_5638_MOESM5_ESM.xlsx (11 kb)
Supplementary material 5 (XLSX 11 kb)
10620_2019_5638_MOESM6_ESM.xlsx (22 kb)
Supplementary material 6 (XLSX 22 kb)

References

  1. 1.
    Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112:18.CrossRefGoogle Scholar
  2. 2.
    Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011;141:1572–1585.CrossRefGoogle Scholar
  3. 3.
    Gabbs M, Leng S, Devassy JG, Monirujjaman M, Aukema HM. Advances in our understanding of oxylipins derived from dietary PUFAs. Adv Nutr (Bethesda, Md.). 2015;6:513–540.CrossRefGoogle Scholar
  4. 4.
    Buczynski MW, Dumlao DS, Dennis EA. Thematic review series: proteomics. An integrated omics analysis of eicosanoid biology. J Lipid Res. 2009;50:1015–1038.CrossRefGoogle Scholar
  5. 5.
    Arnold C, Konkel A, Fischer R, Schunck W-H. Cytochrome P450–dependent metabolism of ω-6 and ω-3 long-chain polyunsaturated fatty acids. Pharmacol Rep. 2010;62:536–547.CrossRefGoogle Scholar
  6. 6.
    Barquissau V, Ghandour RA, Ailhaud G, et al. Control of adipogenesis by oxylipins, GPCRs and PPARs. Biochimie. 2017;136:3–11.CrossRefGoogle Scholar
  7. 7.
    Caligiuri SPB, Parikh M, Stamenkovic A, Pierce GN, Aukema HM. Dietary modulation of oxylipins in cardiovascular disease and aging. Am J Physiol Heart Circ Physiol. 2017;313:H903–H918.CrossRefGoogle Scholar
  8. 8.
    Tourdot BE, Ahmed I, Holinstat M. The emerging role of oxylipins in thrombosis and diabetes. Front Pharmacol. 2014;4:176.CrossRefGoogle Scholar
  9. 9.
    Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science. 2001;294:1871.CrossRefGoogle Scholar
  10. 10.
    Yeung J, Hawley M, Holinstat M. The expansive role of oxylipins on platelet biology. J Mol Med (Berlin, Germany). 2017;95:575–588.CrossRefGoogle Scholar
  11. 11.
    Wagner D, Westover K, Simmons DL. Nonsteroidal anti-inflammatory drugs, acetaminophen, cyclooxygenase 2, and fever. Clin Infect Dis. 2000;31:S211–S218.CrossRefGoogle Scholar
  12. 12.
    Liu MC, Dubé LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: A 6-month randomized multicenter trial. J Allergy Clin Immunol. 1996;98:859–871.CrossRefGoogle Scholar
  13. 13.
    Zhang W, Zhong W, Sun Q, Sun X, Zhou Z. Hepatic overproduction of 13-HODE due to ALOX15 upregulation contributes to alcohol-induced liver injury in mice. Sci Rep. 2017;7:8976.CrossRefGoogle Scholar
  14. 14.
    Feldstein AE, Lopez R, Tamimi TA-R, et al. Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Lipid Res. 2010;51:3046–3054.CrossRefGoogle Scholar
  15. 15.
    Ball SA, Tennen H, Poling JC, Kranzler HR, Rounsaville BJ. Personality, temperament, and character dimensions and the DSM-IV personality disorders in substance abusers. J Abnorm Psychol. 1997;106:545–553.CrossRefGoogle Scholar
  16. 16.
    Brandl K, Hartmann P, Jih LJ, et al. Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis. J Hepatol. 2018;69:396–405.CrossRefGoogle Scholar
  17. 17.
    Nguyen-Khac E, Thiele M, Voican C, et al. Non-invasive diagnosis of liver fibrosis in patients with alcohol-related liver disease by transient elastography: an individual patient data meta-analysis. Lancet Gastroenterol Hepatol. 2018;3:614–625.CrossRefGoogle Scholar
  18. 18.
    Salavrakos M, Piessevaux H, Komuta M, Lanthier N, Starkel P. Fibroscan reliably rules out advanced liver fibrosis and significant portal hypertension in alcoholic patients. J Clin Gastroenterol. 2018.  https://doi.org/10.1097/MCG.0000000000001119.Google Scholar
  19. 19.
    Buzzetti E, Lombardi R, De Luca L, Tsochatzis EA. Noninvasive assessment of fibrosis in patients with nonalcoholic fatty liver disease. Int J Endocrinol. 2015;2015:343828.CrossRefGoogle Scholar
  20. 20.
    Eddowes PJ, Sasso M, Allison M, et al. Accuracy of FibroScan controlled attenuation parameter and liver stiffness measurement in assessing steatosis and fibrosis in patients with non-alcoholic fatty liver disease. Gastroenterology. 2019;​156:1717–1730.CrossRefGoogle Scholar
  21. 21.
    Caussy C, Alquiraish MH, Nguyen P, et al. Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis. Hepatology. 2018;67:1348–1359.CrossRefGoogle Scholar
  22. 22.
    Karlas T, Petroff D, Sasso M, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol. 2017;66:1022–1030.CrossRefGoogle Scholar
  23. 23.
    Leclercq S, Matamoros S, Cani PD, et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci USA. 2014;111:E4485–E4493.CrossRefGoogle Scholar
  24. 24.
    Shearer GC, Harris WS, Pedersen TL, Newman JW. Detection of omega-3 oxylipins in human plasma and response to treatment with omega-3 acid ethyl esters. J Lipid Res. 2010;51:2074–2081.CrossRefGoogle Scholar
  25. 25.
    Luria A, Weldon SM, Kabcenell AK, et al. Compensatory mechanism for homeostatic blood pressure regulation in Ephx2 gene-disrupted mice. J Biol Chem. 2007;282:2891–2898.CrossRefGoogle Scholar
  26. 26.
    Barupal DK, Fiehn O. Chemical similarity enrichment analysis (ChemRICH) as alternative to biochemical pathway mapping for metabolomic datasets. Sci Rep. 2017;7:14567.CrossRefGoogle Scholar
  27. 27.
    Warner DR, Liu H, Ghosh Dastidar S, et al. Ethanol and unsaturated dietary fat induce unique patterns of hepatic ω-6 and ω-3 PUFA oxylipins in a mouse model of alcoholic liver disease. PloS One. 2018;13:e0204119.CrossRefGoogle Scholar
  28. 28.
    Lazic M, Inzaugarat ME, Povero D, et al. Reduced dietary omega-6 to omega-3 fatty acid ratio and 12/15-lipoxygenase deficiency are protective against chronic high fat diet-induced steatohepatitis. PloS one. 2014;9:e107658.CrossRefGoogle Scholar
  29. 29.
    Puri P, Xu J, Vihervaara T, et al. Alcohol produces distinct hepatic lipidome and eicosanoid signature in lean and obese. J Lipid Res. 2016;57:1017–1028.CrossRefGoogle Scholar
  30. 30.
    Puri P, Wiest MM, Cheung O, et al. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology (Baltimore, Md.). 2009;50:1827–1838.CrossRefGoogle Scholar
  31. 31.
    Zein CO, Lopez R, Fu X, et al. Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism. Hepatology (Baltimore, Md.). 2012;56:1291–1299.CrossRefGoogle Scholar
  32. 32.
    Kirpich IA, Feng W, Wang Y, et al. The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease. Alcohol Clin Exp Res. 2012;36:835–846.CrossRefGoogle Scholar
  33. 33.
    Noverr MC, Erb-Downward JR, Huffnagle GB. Production of eicosanoids and other oxylipins by pathogenic eukaryotic microbes. Clin Microbiol Rev. 2003;16:517–533.CrossRefGoogle Scholar
  34. 34.
    Tsitsigiannis DI, Keller NP. Oxylipins as developmental and host–fungal communication signals. Trends Microbiol. 2007;15:109–118.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Bei Gao
    • 1
  • Sonja Lang
    • 1
  • Yi Duan
    • 1
    • 2
  • Yanhan Wang
    • 1
    • 2
  • Debbie L. Shawcross
    • 3
  • Alexandre Louvet
    • 4
  • Philippe Mathurin
    • 4
  • Samuel B. Ho
    • 1
    • 2
  • Peter Stärkel
    • 5
  • Bernd Schnabl
    • 1
    • 2
    Email author
  1. 1.Department of MedicineUniversity of California San DiegoLa JollaUSA
  2. 2.Department of MedicineVA San Diego Healthcare SystemSan DiegoUSA
  3. 3.Institute of Liver Studies, King’s College London School of Medicine at King’s College HospitalKing’s College HospitalLondonUK
  4. 4.Service des Maladies de L’appareil Digestif et Unité INSERMHôpital HuriezLilleFrance
  5. 5.St. Luc University HospitalUniversité Catholique de LouvainBrusselsBelgium

Personalised recommendations