4 research outputs found
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 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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Clinical, histological and molecular profiling of different stages of alcohol-related liver disease.
Alcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking. Two large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed. Age and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and ductular reaction were more frequent among AH patients. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. While ndALD was characterised by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism. Despite comparable alcohol intake, AH patients presented with worse liver function compared with ndALD patients. Bilirubinostasis, severe fibrosis and ductular reaction were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared with ndALD patients
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 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
Clinical, histological and molecular profiling of different stages of alcohol-related liver disease
Objective Alcohol-related liver disease (ALD) ranges from
never-decompensated ALD (ndALD) to the life-threatening decompensated
phenotype, known as alcohol-related hepatitis (AH). A multidimensional
study of the clinical, histological and molecular features of these
subtypes is lacking. Design Two large cohorts of patients were recruited
in an international, observational multicentre study: a retrospective
cohort of patients with ndALD (n=110) and a prospective cohort of
patients with AH (n=225). Clinical, analytical, immunohistochemistry and
hepatic RNA microarray analysis of both disease phenotypes were
performed. Results Age and mean alcohol intake were similar in both
groups. AH patients had greater aspartate amino transferase/alanine
amino transferase ratio and lower gamma-glutamyl transferase levels than
in ndALD patients. Patients with AH demonstrated profound liver failure
and increased mortality. One-year mortality was 10% in ndALD and 50%
in AH. Histologically, steatosis grade, ballooning and pericellular
fibrosis were similar in both groups, while advanced fibrosis,
Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration
and ductular reaction were more frequent among AH patients.
Transcriptome analysis revealed a profound gene dysregulation within
both phenotypes when compare to controls. While ndALD was characterised
by deregulated expression of genes involved in matrisome and immune
response, the development of AH resulted in a marked deregulation of
genes involved in hepatocyte reprogramming and bile acid metabolism.
Conclusions Despite comparable alcohol intake, AH patients presented
with worse liver function compared with ndALD patients.
Bilirubinostasis, severe fibrosis and ductular reaction were prominent
features of AH. AH patients exhibited a more profound deregulation of
gene expression compared with ndALD patients