Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.
Sci Rep. 2016 Oct 18;6:35610. doi: 10.1038/srep35610.
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.
酒精性肝炎 (AH) 是最严重的酒精性肝病形式，目前尚无有效的治疗方法。AH 患者表现出肝细胞增殖受损、无效胆管细胞扩张和内毒素 (LPS) 水平升高。目前尚不清楚 LPS 是否介导胆管细胞扩张。我们进行了转录组研究，发现角蛋白 23 (KRT23) 是一种新的胆管细胞标志物。KRT23 的表达与死亡率和 LPS 血清水平相关。在人和小鼠祖细胞、肝切片和肝损伤 TLR4 KO 小鼠中评估了 LPS-TLR4 通路在胆管细胞扩张中的作用。在 AH 患者中，胆管细胞扩张与门静脉高压和胶原表达相关。胆管细胞的功能研究表明，KRT23 调节胶原表达。这些结果支持 LPS-TLR4 通路在促进 AH 中胆管反应中的作用。旨在降低 AH 患者 LPS 血清水平的策略可能通过防止胆管反应的发展而产生有益效果。
