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

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...

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Autores: Argemí, J. (Josepmaria)|||/items/cc37a6af-13a2-4fe0-846c-4725cca0ae72, Latasa, M.U. (María Ujué)|||/items/e1e74596-1598-4722-a96a-7bdd7cdec356, Atkinson, S.R. (Stephen R.)|||/items/8b751fd8-eeb7-41cc-a5c4-75f9257ddb53, Blokhin, I.O. (Ilya O.)|||/items/ac6bcd78-1de0-4d28-9921-00ba9a1aa2bc, Massey, V. (Veronica)|||/items/4c913389-7f50-47cb-b07f-0c15096c265f, Gue, J.P. (Joel P.)|||/items/2a7b2cc4-ac20-4c6f-93c2-30c89b2cc8ab, Cabezas, J. (Joaquín)|||/items/f3d8d3e7-d1cb-4ffe-8502-62ffb713e997, Lozano, J.J. (Juan J.)|||/items/16ab84f4-d236-4b74-8ae6-7aed1c5f99e5, Van-Booven, D. (Derek)|||/items/626d429c-6713-408d-b2a0-2841a739b851, Bell, A. (Aaron)|||/items/3e39d717-fb25-424a-9562-9179acb0dfbe, Cao, S. (Sheng)|||/items/6791febc-83df-4eba-839b-e2e0d14ce1b0, Vernetti, L.A. (Lawrence A.)|||/items/b5b7a0be-c2c5-4f44-9e28-b73dda8fd2c4, Arab, J.P. (Juan P.)|||/items/9015bde7-706e-4ec6-aa45-a9ba24d69409, Ventura-Cots, M. (Meritxell)|||/items/c47ee058-fe88-46ed-8518-857e3e6bff00, Edmunds, L.R. (Lia R.)|||/items/545d34a7-6e63-4904-855b-809292260288, Fondevilla, C. (Constantino)|||/items/887ef9bd-4c62-4391-a404-7d0ba4f9adc5, Stärkel, P. (Peter)|||/items/67314cff-6dcc-4a3f-889b-bc2df500307f, Dubuquoy, L. (Laurent)|||/items/5b5e4646-71c8-4d72-84ce-27f244c31e77, Louvet, A. (Alexandre)|||/items/c3da4485-a217-4d3d-8d03-eef850a9dcc4, Odena, G. (Gemma)|||/items/04c51c11-0409-4de6-965f-b49b6416639e, Gómez, J.L. (Juan L.)|||/items/1d25ac46-9054-4cd3-94d8-885ed12254e5, Aragón, T. (Tomás)|||/items/25815aa1-2185-482b-b38e-b26dca1f83d9, Altamirano, J. (Jose)|||/items/6ece5d5b-2d37-474e-a094-666a03bb36d4, Caballeria, J. (Juan)|||/items/56e3d84d-13f7-4138-b036-ec725cc9a622, Jurczak, M.J. (Michael J.)|||/items/271f443a-e8a1-40d5-a46f-05a12de1f4dd, Taylor, D.L. (D. Lansing)|||/items/88bda9a2-cc65-4a93-b83e-cc82073d5193, Berasain-Lasarte, C. (Carmen)|||/items/f1d61c19-1753-4442-a3fd-cc90220e84a0, Wahlestedt, C. (Claes)|||/items/d26a7933-a1c9-4903-945f-1bf146435ced, Monga, S.P. (Satdarshan P.)|||/items/068189ef-613a-48f4-9e6d-fc7ae6b5a6da, Morgan, M.Y. (Marsha Y.)|||/items/372c4efc-d8c4-46e5-a61d-7582374eec63, Sancho-Bru, P. (Pau)|||/items/2ff85ad0-c7d1-404a-9c20-a5ea58963258, Mathurin, P. (Philippe)|||/items/7adee2eb-664a-44e8-9f45-26c0d710849e, Furuya, S. (Shinji)|||/items/fedb6076-3a3f-4ec3-900a-aa3046ff684c, Lackner, C. (Carolin)|||/items/c470f8ef-ff06-4436-be78-b6a3c2363c30, Rusyn, I. (Ivan)|||/items/bcff7779-fe3d-4f1d-8ccd-2d466dd748f1, Shah, V.H. (Vijay H.)|||/items/d8bdc6d4-63ee-42fe-b4d2-27c16f01e077, Thursz, M.R. (Mark R.)|||/items/820ae838-e8ac-4ee5-ab72-59a26d682a3c, Mann, J. (Jelena)|||/items/62541d21-a7b1-4e3b-a579-eb63b7469880, Avila, M.A. (Matías Antonio)|||/items/3ad9abbb-c18d-445b-86cf-cb76be15419f, Bataller, R. (Ramón)|||/items/3aa26118-7542-46cc-a8df-57e869a7e310
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/62977
Acceso en línea:https://hdl.handle.net/10171/62977
Access Level:acceso abierto
Palabra clave:Materias Investigacion::Ciencias de la Salud::Hepatología
Hepatología
Descripción
Sumario: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). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α 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 HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.

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