11 - ago. - 2019
Liver disease due to fat deposition is an emerging entity in liver pathology. The most frequent causes are alcohol consumption and / or obesity / metabolic syndrome among others (drug toxicity, autoimmune diseases etc).
Dr. Cabezas with the support of Dr. Crespo, Head of the Digestive System Service and thanks to the support of the Spanish Association for the Study of the Liver, through the 2015 Juan Rodes Scholarship, was able to enjoy a one-year stay in the United States under the tutelage of Dr. Ramón Bataller at the University of North Carolina at Chapel Hill. Currently, Dr. Bataller is the head of Hepatology at Pittsburgh Liver Research Center.
Dr. Bataller focuses his line of research on alcoholic liver disease, specifically Alcoholic Hepatitis, the most advanced expression of alcoholic liver disease with high mortality. To do this, within the collaborative grant (1U01AA021908-01, MOLECULAR SUBTYPES FOR TARGETED THERAPIES IN ALCOHOLIC HEPATITIS) has allowed multidisciplinary and cross-sectional research on alcoholic hepatitis. Among his collaborators, in this work (1), Prof. Wajahat Mehal of Yale University stands out.
Alcoholic liver disease at its best, called Alcoholic Hepatitis, determines its progression by liver inflammation from fat accumulation and direct damage / through inflammatory mediators - what we call steatohepatitis. This "sterile" inflammation, since it is not caused by microorganisms, is induced by liver damage and is maintained by transcription factors such as HIF-1alpha induced by oxidative stress. Digoxin, in addition to its known cardiological effect, is known as an inhibitor of this transcription factor, but its hepatic effect had not been evaluated.
The digoxin through PKM2 (Isoform 2 of pyruvate kinase) to which it binds, and inhibits the transcription capacity of HIF-1alpha. And this function is carried out through epigenetic mechanisms such as chromatin remodeling. Therefore, it is shown that PKM2 can be a therapeutic target to treat steatohepatitis.
Going further in the research of Dr. Bataller's group, Dr. Cabezas was part of the first results of deep sequencing of total RNA from liver tissue samples in patients with alcoholic hepatitis. As a result of this collaboration, a manuscript was recently published in Nature Communications (2) that shows the role of hepatic transcription factors, highlighting HNF4A. This is a complete work that uses the latest techniques of high throughput data and bioinformatic analysis to determine the role of HNF4A, specifically the P2 subunit and its metabolic implications in hepatocyte, mediated by TGFbeta of patients with alcoholic hepatitis. On the other hand, in addition, epigenetic studies (methylation and chromatin remodeling) were performed using the aforementioned techniques supported by the Jelena Mann Laboratory in New Castle and Vijay Shah of the Mayo Clinic in Rochester. To confirm the findings generated by the bioinformatics techniques, we had the collaboration of Dr. Ávila del CIMA, Pamplona. The part of the study for the SNP analysis was supported by the group of Mark Thursz of the King College London, lead author of the STOPHA trial publishing in the New England Journal of Medicine on the treatment of alcoholic hepatitis.
This work opens the door for the treatment of alcoholic hepatitis with targets that focus on the modification of transcription factors and epigenetic changes that allow recovering the function of hepatocytes mediated by HNF4A.
Dr. Cabezas during his stay in the Laboratory of Dr. Bataller had the opportunity to carry out another series of works and collaborations described below:
- Review of epigenetics in liver fibrosis (3).
- Value of renal failure in alcoholic hepatitis (4).
- Impact of renal function in the patient transplanted due to alcoholic liver disease (5).
- Editorial of a trial with SAME (S-Adenosin-Methionine) in alcoholic hepatitis (6).
- Importance of alcoholic liver disease in relation to the other main causes of liver disease (7).
- Role of TLRs in alcoholic liver disease, specifically TLR7 and how it is modulated by microRNA (let-7), another epigenetic mechanism to be taken into account (8).
- Review of biomarkers of alcohol consumption (9).
- Perspective of the Dry January of the United Kingdom to encourage the abandonment of alcohol abuse (10).
- Ouyang X, Han SN, Zhang JY, Dioletis E, Nemeth BT, Pacher P, Feng D, Bataller R, Cabezas J, Starkel P, Caballeria J, Pongratz RL, Cai SY, Schnabl B, Hoque R, Chen Y, Yang WH, Garcia-Martinez I, Wang FS, Gao B, Torok NJ, Kibbey RG, Mehal WZ. Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1alpha Transactivation in Steatohepatitis. Cell Metab. 2018;27(2):339-50 e3. Epub 2018/02/08. doi: 10.1016/j.cmet.2018.01.007. PubMed PMID: 29414684; PMCID: PMC5806149.
- Argemi J, Latasa MU, Atkinson SR, Blokhin IO, Massey V, Gue JP, Cabezas J, Lozano JJ, Van Booven D, Bell A, Cao S, Vernetti LA, Arab JP, Ventura-Cots M, Edmunds LR, Fondevilla C, Stärkel P, Dubuquoy L, Louvet A, Odena G, Gomez JL, Aragon T, Altamirano J, Caballeria J, Jurczak MJ, Taylor DL, Berasain C, Wahlestedt C, Monga SP, Morgan MY, Sancho-Bru P, Mathurin P, Furuya S, Lackner C, Rusyn I, Shah VH, Thursz MR, Mann J, Avila MA, Bataller R. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis. Nature communications. 2019;10(1):3126. doi: 10.1038/s41467-019-11004-3.
- Massey V, Cabezas J, Bataller R. Epigenetics in Liver Fibrosis. Seminars in liver disease. 2017;37(3):219-30. Epub 2017/08/29. doi: 10.1055/s-0037-1605371. PubMed PMID: 28847033.
- Sujan R, Cruz-Lemini M, Altamirano J, Simonetto DA, Maiwall R, Axley P, Richardson T, Desai V, Cabezas J, Vargas V, Kamath PS, Shah VH, Sarin SK, Bataller R, Singal AK. A Validated Score Predicts Acute Kidney Injury and Survival in Patients With Alcoholic Hepatitis. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2018;24(12):1655-64. Epub 2018/08/29. doi: 10.1002/lt.25328. PubMed PMID: 30153377.
- Cheong J, Galanko JA, Arora S, Cabezas J, Ndugga NJ, Lucey MR, Hayashi PH, Barritt AS, Bataller R. Reduced impact of renal failure on the outcome of patients with alcoholic liver disease undergoing liver transplantation. Liver Int. 2017;37(2):290-8. Epub 2016/06/04. doi: 10.1111/liv.13182. PubMed PMID: 27258535; PMCID: PMC5136341.
- Cabezas J, Bataller R. Alcoholic hepatitis: should we combine old drugs for better results? Hepatol Int. 2016;10(6):851-3. Epub 2016/10/28. doi: 10.1007/s12072-016-9768-8. PubMed PMID: 27638331.
- Ndugga N, Lightbourne TG, Javaherian K, Cabezas J, Verma N, Barritt ASt, Bataller R. Disparities between research attention and burden in liver diseases: implications on uneven advances in pharmacological therapies in Europe and the USA. BMJ open. 2017;7(3):e013620. Epub 2017/03/25. doi: 10.1136/bmjopen-2016-013620. PubMed PMID: 28336739; PMCID: PMC5372160.
- Massey VL, Qin L, Cabezas J, Caballeria J, Sancho-Bru P, Bataller R, Crews FT. TLR7-let-7 Signaling Contributes to Ethanol-Induced Hepatic Inflammatory Response in Mice and in Alcoholic Hepatitis. Alcohol Clin Exp Res. 2018;42(11):2107-22. Epub 2018/08/14. doi: 10.1111/acer.13871. PubMed PMID: 30103265; PMCID: PMC6282707.
- Cabezas J, Lucey MR, Bataller R. Biomarkers for monitoring alcohol use. Clinical Liver Disease. 2016;8(3):59-63. doi: 10.1002/cld.571.
- Cabezas J, Bataller R. Alcoholic liver disease: New UK alcohol guidelines and Dry January: enough to give up boozing? Nat Rev Gastroenterol Hepatol. 2016;13(4):191-2. Epub 2016/03/10. doi: 10.1038/nrgastro.2016.39. PubMed PMID: 26956065.