Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

被引：143

作者：

Argemie, Josepmaria ^{[1
,2
]}

Latasa, Maria U. ^{[3
]}

Atkinson, Stephen R. ^{[4
]}

Blokhin, Ilya O. ^{[5
,6
]}

Massey, Veronica ^{[7
,8
]}

Gue, Joel P. ^{[1
]}

Cabezas, Joaquin ^{[7
,8
,9
]}

Lozano, Juan J. ^{[10
,11
]}

Van Booven, Derek ^{[12
]}

Bell, Aaron ^{[13
,14
]}

Cao, Sheng ^{[15
]}

Vernetti, Lawrence A. ^{[16
]}

Arab, Juan P. ^{[15
,17
]}

Ventura-Cots, Meritxell ^{[1
]}

Edmunds, Lia R. ^{[18
]}

Fondevilla, Constantino ^{[19
]}

Starkel, Peter ^{[20
,21
]}

Dubuquoy, Laurent ^{[22
]}

Louvet, Alexandre ^{[22
]}

Odena, Gemma ^{[7
,8
]}

Gomez, Juan L. ^{[13
,14
]}

Aragon, Tomas ^{[23
]}

Altamirano, Jose ^{[24
]}

Caballeria, Juan ^{[10
,11
]}

Jurczak, Michael J. ^{[18
]}

Taylor, D. Lansing ^{[16
]}

Berasain, Carmen ^{[3
,10
]}

Wahlestedt, Claes ^{[5
,6
]}

Mongv, Satdarshan P. ^{[13
,14
]}

Morgan, Marsha Y. ^{[25
]}

Sancho-Bru, Pau ^{[10
,11
]}

Mathurin, Philippe ^{[22
]}

Furuya, Shinji ^{[26
]}

Lackner, Carolin ^{[27
]}

Rusyn, Ivan ^{[26
]}

Shah, Vijay H. ^{[15
]}

Thursz, Mark R. ^{[4
]}

Mann, Jelena ^{[28
]}

Avila, Matias A. ^{[3
,10
]}

Bataller, Ramon ^{[1
,7
,8
]}

机构：

[1] UPMC, Pittsburgh Liver Res Ctr, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15261 USA

[2] Univ Navarra, Clin Univ Navarra, Liver Unit, Pamplona 31008, Spain

[3] Univ Navarra, Ctr Appl Med Res CIMA, Hepatol Program, Pamplona 31008, Spain

[4] Imperial Coll London, Dept Surg & Canc, Div Digest Dis, London SW7 2AZ, England

[5] Univ Miami, Miller Sch Med, Ctr Therapeut Innovat, Miami, FL 33136 USA

[6] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA

[7] Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC 27516 USA

[8] Univ N Carolina, Dept Nutr, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27516 USA

[9] Marques de Valdecilla Univ Hosp, Dept Hepatol, Santander 39008, Spain

[10] Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid 28029, Spain

[11] Inst Invest Biomed August Pi i Sunyer IDIBAPS, Barcelona 08036, Spain

[12] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA

[13] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh Liver Res Ctr, Pittsburgh, PA 15261 USA

[14] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh Liver Res Ctr, Pittsburgh, PA 15261 USA

[15] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA

[16] Univ Pittsburgh, Drug Discovery Inst, Dept Computat & Syst Biol, Pittsburgh, PA 15261 USA

[17] Pontificia Univ Catolica Chile, Dept Gastroenterol, Escuela Med, Santiago, Chile

[18] Univ Pittsburgh, Ctr Metab & Mitochondrial Med, Dept Med, Div Endocrinol & Metab, Pittsburgh, PA 15261 USA

[19] Univ Barcelona, Hosp Clin, Dept Surg, Liver Transplant Unit, E-08036 Barcelona, Spain

[20] Catholic Univ Louvain, Clin Univ St Luc, Serv Hepatogastroenterol, B-1200 Brussels, Belgium

[21] Catholic Univ Louvain, Lab Hepatogastroenterol, Inst Rech Expt & Clin, B-1200 Brussels, Belgium

[22] Univ Lille, Serv Malad Appareil Digestif, CHU Lille, INSERM LIRIC UMR995, F-59000 Lille, France

[23] Univ Navarra, Ctr Appl Med Res, Dept Gene Therapy & Regulat, Pamplona 31008, Spain

[24] Hosp Quiron Salud, Vall dHebron Inst Recerca, Dept Internal Med, Liver Unit,Internal Med Dept, Barcelona 08035, Spain

[25] UCL, UCL Inst Liver & Digest Hlth, Div Med, Royal Free Campus, London WC1E 6BT, England

[26] Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77845 USA

[27] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria

[28] Newcastle Univ, Fac Med Sci, Inst Cellular Med, Newcastle Fibrosis Res Grp, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

TO-MESENCHYMAL TRANSITION; GENOME-WIDE ASSOCIATION; FACTOR 4-ALPHA ISOFORMS; LIVER-DISEASE; DNA METHYLATION; SCORING SYSTEM; GROWTH; SRC; GLUCONEOGENESIS; PENTOXIFYLLINE;

D O I：

10.1038/s41467-019-11004-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGF beta 1 is a key upstream transcriptome regulator in AH and induces the use of HNF4 alpha P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4 alpha are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4 alpha-dependent gene expression. We conclude that targeting TGF beta 1 and epigenetic drivers that modulate HNF4 alpha-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.

引用

页数：19

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