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.

Charles University 1st Faculty of Medicine Institute of Physiology Prague Czech Republic

Charles University and General University Hospital Prague 1st Faculty of Medicine Institute of Biology and Medical Genetics Prague Czech Republic

Clinical and Transplant Pathology Centre Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Hepatogastroenterology Institute for Clinical and Experimental Medicine Prague Czech Republic

Experimental Medicine Centre Institute for Clinical and Experimental Medicine Prague Czech Republic

Zobrazit více v PubMed

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. PubMed

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 PubMed

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 PubMed PMC

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 PubMed

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. PubMed

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. PubMed

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. PubMed

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 PubMed PMC

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 PubMed PMC

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 PubMed DOI PMC

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 PubMed DOI PMC

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: 10.1038/ncomms3883 PubMed DOI PMC

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 PubMed

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 PubMed

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: 10.1016/j.jhep.2018.08.008 PubMed DOI

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. PubMed

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 PubMed

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 PubMed PMC

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: 10.1038/nature10486 PubMed DOI PMC

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 PubMed PMC

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: 10.1053/j.gastro.2018.12.036 PubMed DOI PMC

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 PubMed

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 PubMed

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 PubMed