Mechanisms of ductular reaction in non-alcoholic steatohepatitis

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a disease spectrum caused in part by insulin resistance and genetic predisposition. This disease is primarily characterized by excessive lipid accumulation in hepatocytes in the absence of alcohol abuse and other causes of liver damage. Histologically, NAFLD is divided into several periods: simple steatosis, non-alcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. With the increasing prevalence of obesity and hyperlipidemia, NAFLD has become the main cause of chronic liver disease worldwide. As a result, the pathogenesis of this disease is drawing increasing attention. Ductular reaction (DR) is a reactive bile duct hyperplasia caused by liver injury that involves hepatocytes, cholangiocytes, and hepatic progenitor cells. Recently, DR is shown to play a pivotal role in simple steatosis progression to NASH or liver fibrosis, providing new research and treatment options. This study reviews several DR signaling pathways, including Notch, Hippo/YAP-TAZ, Wnt/β-catenin, Hedgehog, HGF/c-Met, and TWEAK/Fn14, and their role in the occurrence and development of NASH.

Keywords: Ductular reaction; Mechanisms; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Signaling pathways.

Figure 1

The different compartments of the ductular reaction, including hepatocyte self-proliferation and transdifferentiation, hepatic progenitor cell differentiation, and cholangiocyte proliferation and transdifferention. HPC: Hepatic progenitor cell.

Figure 2

A series of highly conserved signaling pathways in the ductular reaction which promotes the occurrence of non-alcoholic fatty liver disease and aggravates the prognosis of non-alcoholic steatohepatitis (Created with BioRender.com). A: The Notch signaling pathway regulates expression of genes, such as the Hes and Hey-related family, to determine cell differentiation and function, maintain liver homeostasis, repair liver damage, and regulate liver metabolism, inflammation, and cancer; B: The Hippo/YAP-TAZ signaling pathway can regulate liver size, metabolism, cell proliferation, cell migration, the epithelial-mesenchymal transition, and formation of the extracellular matrix and cytoskeleton formation, etc; C: The Wnt/β-catenin signaling pathway affects liver development and physiological functions of all liver disease stages, from initial injury and inflammation to fibrosis, cirrhosis and tumor occurrence; D: The hedgehog signaling pathway affects cell proliferation, migration, and differentiation; E: The HGF/c-Met signaling pathway activates multiple intracellular signaling pathways and affect cell proliferation, migration, and differentiation; F: The TWEAK/Fn14 signaling pathway regulates tissue inflammation and damage repair in addition to cell survival and death. HPC: Hepatic progenitor cell; NASH: Non-alcoholic steatohepatitis.