Serum miR-33a is associated with steatosis and inflammation in patients with non-alcoholic fatty liver disease after liver transplantation
Autoři:
Denisa Erhartova aff001; Monika Cahova aff003; Helena Dankova aff003; Marie Heczkova aff003; Irena Mikova aff001; Eva Sticova aff004; Julius Spicak aff001; Ondrej Seda aff005; Pavel Trunecka aff001
Působiště autorů:
Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
aff001; Charles University, First Faculty of Medicine, Institute of Physiology, Prague, Czech Republic
aff002; Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
aff003; Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
aff004; Charles University and General University Hospital in Prague, First Faculty of Medicine, Institute of Biology and Medical Genetics, Prague, Czech Republic
aff005
Vyšlo v časopise:
PLoS ONE 14(11)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0224820
Souhrn
Background & aims
MiR-33a has emerged as a critical regulator of lipid homeostasis in the liver. Genetic deficiency of miR-33a aggravates liver steatosis in a preclinical model of non-alcoholic fatty liver disease (NAFLD), and relative expression of miR-33a is increased in the livers of patients with non-alcoholic steatohepatitis (NASH). It was unknown whether miR-33a is detectable in the serum of patients with NAFLD. We sought to determine whether circulating miR-33a is associated with histological hepatic steatosis, inflammation, ballooning or fibrosis, and whether it could be used as a serum marker in patients with NAFLD/NASH.
Methods
We analysed circulating miR-33a using quantitative PCR in 116 liver transplant recipients who underwent post-transplant protocol liver biopsy. Regression analysis was used to determine association of serum miR-33a with hepatic steatosis, inflammation, ballooning and fibrosis in liver biopsy.
Results
Liver graft steatosis and inflammation, but not ballooning or fibrosis, were significantly associated with serum miR-33a, dyslipidemia and insulin resistance markers on univariate analysis. Multivariate analysis showed that steatosis was independently associated with serum miR-33a, ALT, glycaemia and waist circumference, whereas inflammation was independently associated with miR-33a, HbA1 and serum triglyceride levels. Receiver operating characteristic analysis showed that exclusion of serum miR-33a from multivariate analysis resulted in non-significant reduction of prediction model accuracy of liver steatosis or inflammation.
Conclusions
Our data indicate that circulating miR-33a is an independent predictor of liver steatosis and inflammation in patients after liver transplantation. Although statistically significant, its contribution to the accuracy of prediction model employing readily available clinical and biochemical variables was limited in our cohort.
Klíčová slova:
Biopsy – Fatty liver – Fibrosis – Inflammation – Lipid metabolism – Liver transplantation – MicroRNAs – Steatosis
Zdroje
1. Younossi ZM, Marchesini G, Pinto-Cortez H, Petta S. Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: Implications for Liver Transplantation. Transplantation. 2019;103(1):22–7.
2. Diehl AM, Day C. Nonalcoholic Steatohepatitis. N Engl J Med [Internet]. 2018;378(8):781. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29466150
3. Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science [Internet]. 2011 Jun 24;332(6037):1519–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21700865
4. Hejlova I, Honsova E, Sticova E, Lanska V, Hucl T, Spicak J, et al. Prevalence and risk factors of steatosis after liver transplantation and patient outcomes. Liver Transpl [Internet]. 2016;22(5):644–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26707008
5. Dumortier J, Giostra E, Belbouab S, Morard I, Guillaud O, Spahr L, et al. Non-alcoholic fatty liver disease in liver transplant recipients: Another story of seed and soil. Am J Gastroenterol. 2010;105(3):613–20.
6. Narayanan P, Mara K, Izzy M, DIerkhising R, Heimbach J, Allen AM, et al. Recurrent or de Novo Allograft Steatosis and Long-term Outcomes after Liver Transplantation. Transplantation. 2019;103(1):E14–21.
7. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84.
8. Rottiers V, Näär AM. MicroRNAs in metabolism and metabolic disorders. Nat Rev Mol Cell Biol [Internet]. 2012 Mar 22;13(4):239–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22436747
9. Szabo G, Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol [Internet]. 2013 Sep 21;10(9):542–52. Available from: http://www.nature.com/articles/nrgastro.2013.87
10. Rayner KJ, Suarez Y, Davalos A, Parathath S, Fitzgerald ML, Tamehiro N, et al. MiR-33 Contributes to the Regulation of Cholesterol Homeostasis. Science (80-) [Internet]. 2010 Jun 18;328(5985):1570–3. Available from: http://www.sciencemag.org/cgi/doi/10.1126/science.1189862
11. Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Cohen DE, Gerszten RE, et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science [Internet]. 2010 Jun 18;328(5985):1566–9. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.1005191107
12. Horie T, Nishino T, Baba O, Kuwabara Y, Nakao T, Nishiga M, et al. MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice. Nat Commun [Internet]. 2013;4:2883. Available from: http://dx.doi.org/10.1038/ncomms3883
13. Vega-Badillo J, Gutiérrez-Vidal R, Hernández-Pérez HA, Villamil-Ramírez H, León-Mimila P, Sánchez-Muñoz F, et al. Hepatic miR-33a/miR-144 and their target gene ABCA1 are associated with steatohepatitis in morbidly obese subjects. Liver Int [Internet]. 2016;36(9):1383–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26945479
14. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology [Internet]. 2005 Jun;41(6):1313–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15915461
15. Liu C-H, Ampuero J, Gil-Gómez A, Montero-Vallejo R, Rojas Á, Muñoz-Hernández R, et al. miRNAs in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Hepatol [Internet]. 2018 Dec;69(6):1335–48. Available from: https://doi.org/10.1016/j.jhep.2018.08.008
16. Trunečka P, Míková I, Dlouhá D, Hubáček JA, Honsová E, Kolesár L, et al. Donor PNPLA3 rs738409 genotype is a risk factor for graft steatosis. A post-transplant biopsy-based study. Dig Liver Dis. 2018 May 1;50(5):490–5.
17. Míková I, Neřoldová M, Hubáček JA, Dlouhá D, Jirsa M, Honsová E, et al. DONOR PNPLA3 AND TM6SF2 VARIANT ALLELES CONFER ADDITIVE RISKS FOR GRAFT STEATOSIS AFTER LIVER TRANSPLANTATION. Transplantation [Internet]. 2019 Jul 26; Available from: http://www.ncbi.nlm.nih.gov/pubmed/31356578
18. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest [Internet]. 2002 May;109(9):1125–31. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11994399
19. Rayner KJ, Esau CC, Hussain FN, McDaniel AL, Marshall SM, van Gils JM, et al. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature [Internet]. 2011 Oct 19;478(7369):404–7. Available from: http://dx.doi.org/10.1038/nature10486
20. López-Riera M, Conde I, Quintas G, Pedrola L, Zaragoza Á, Perez-Rojas J, et al. Non-invasive prediction of NAFLD severity: a comprehensive, independent validation of previously postulated serum microRNA biomarkers. Sci Rep [Internet]. 2018 Jul 13;8(1):10606. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30006517
21. Castera L, Friedrich-Rust M, Loomba R. Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology [Internet]. 2019;156(5):1264-1281.e4. Available from: https://doi.org/10.1053/j.gastro.2018.12.036
22. McCormack L, Petrowsky H, Jochum W, Mullhaupt B, Weber M, Clavien P-A. Use of Severely Steatotic Grafts in Liver Transplantation. Ann Surg [Internet]. 2007 Dec;246(6):940–8. Available from: https://insights.ovid.com/crossref?an=00000658-200712000-00005
23. Marsman WA, Wiesner RH, Rodriguez L, Batts KP, Porayko MK, Hay JE, et al. Use of fatty donor liver is associated with diminished early patient and graft survival. Transplantation [Internet]. 1996 Nov 15;62(9):1246–51. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8932265
24. Li J, Liu B, Yan L-N, Zuo Y-X, Li B, Zeng Y, et al. Reversal of graft steatosis after liver transplantation: prospective study. Transplant Proc [Internet]. 2009 Nov;41(9):3560–3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19917344
Článek vyšel v časopise
PLOS One
2019 Číslo 11
- Tisícileté topoly, mokří psi, stárnoucí kočky a ospalé octomilky – „jednohubky“ z výzkumu 2024/41
- Jaké jsou aktuální trendy v léčbě karcinomu slinivky?
- Může hubnutí souviset s vyšším rizikem nádorových onemocnění?
- Menstruační krev má značný diagnostický potenciál, mimo jiné u diabetu
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
Nejčtenější v tomto čísle
- A daily diary study on maladaptive daydreaming, mind wandering, and sleep disturbances: Examining within-person and between-persons relations
- A 3’ UTR SNP rs885863, a cis-eQTL for the circadian gene VIPR2 and lincRNA 689, is associated with opioid addiction
- A substitution mutation in a conserved domain of mammalian acetate-dependent acetyl CoA synthetase 2 results in destabilized protein and impaired HIF-2 signaling
- Molecular validation of clinical Pantoea isolates identified by MALDI-TOF
Zvyšte si kvalifikaci online z pohodlí domova
Všechny kurzy