LPS-TLR4 Pathway Mediates Ductular Cell Expansion in Alcoholic Hepatitis.

Gemma Òdena ,Hiroshi Matsushita,Raluca Dumitru,Jiegen Chen,Min You,Dominique Valla,Jian Zou,Oriol Morales-Ibanez,Ekihiro Seki,Daniel Rodrigo-Torres,Vicente Arroyo,José Altamirano ,Pau Sancho‐Bru ,Fulton T Crews ,Pierre‐Emmanuel Rautou ,Silvia Affò ,Juan José Lozano ,Juan Caballería ,Pere Ginés ,Ramón Bataller

doi:10.1038/srep35610

Abstract

Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease for which there are no effective therapies. Patients with AH show impaired hepatocyte proliferation, expansion of inefficient ductular cells and high lipopolysaccharide (LPS) levels. It is unknown whether LPS mediates ductular cell expansion. We performed transcriptome studies and identified keratin 23 (KRT23) as a new ductular cell marker. KRT23 expression correlated with mortality and LPS serum levels. LPS-TLR4 pathway role in ductular cell expansion was assessed in human and mouse progenitor cells, liver slices and liver injured TLR4 KO mice. In AH patients, ductular cell expansion correlated with portal hypertension and collagen expression. Functional studies in ductular cells showed that KRT23 regulates collagen expression. These results support a role for LPS-TLR4 pathway in promoting ductular reaction in AH. Maneuvers aimed at decreasing LPS serum levels in AH patients could have beneficial effects by preventing ductular reaction development.

Highlights

Alcoholic liver disease (ALD) is the main cause of cirrhosis worldwide[1] and the main driver of health expenditure in hospitalized patients with liver disease in the US2
296 genes were dysregulated in alcoholic hepatitis (AH) and non-alcoholic steatohepatitis (NASH) compared to normal livers, while a smaller group of genes were dysregulated in NASH compared to AH (148 upregulated and 102 downregulated, respectively)
Because ALD is characterized by profound epigenetic changes[41] and keratin 23 (KRT23) is sensitive to histone deacetylases (HDAC) inhibition[42], we investigated whether KRT23 expression in ductular cells is governed by histone acetylation in LPCs

Summary

Introduction

Alcoholic liver disease (ALD) is the main cause of cirrhosis worldwide[1] and the main driver of health expenditure in hospitalized patients with liver disease in the US2. It is plausible that increased LPS levels play a role in the expansion of inefficient ductular cells in AH. To test this hypothesis, we conducted a systems biology approach including a comparative transcriptome analysis of liver from patients with AH and non-alcoholic steatohepatitis (NASH) to find novel markers of ductular cells. This keratin was expressed in the ductular reaction in humans and mice Based on these recent data, we hypothesized that the LPS-TLR4 pathway may stimulate the expansion of ductular reaction and regulates the biological properties of ductular cells in AH

Methods

Results

Conclusion