Hedgehog signalling in liver pathophysiology

Abstract

Liver disease remains a leading cause of mortality worldwide despite recent successes in the field of viral hepatitis, because increases in alcohol consumption and obesity are fuelling an epidemic of chronic fatty liver disease for which there are currently no effective medical therapies. About 20% of individuals with chronic liver injury ultimately develop end-stage liver disease due to cirrhosis. Hence, treatments to prevent and reverse cirrhosis in individuals with ongoing liver injury are desperately needed. The development of successful treatments requires an improved understanding of the mechanisms controlling liver disease progression. The liver responds to diverse insults with a conserved wound healing response, suggesting that it might be generally beneficial to optimise pathways that are crucial for effective liver repair. The Hedgehog pathway has emerged as a potential target based on compelling preclinical and clinical data, which demonstrate that it critically regulates the liver's response to injury. Herein, we will summarise evidence of the Hedgehog pathway's role in liver disease and discuss how modulating pathway activity might be applied to improve liver disease outcomes.

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice

“…Under hypoxic conditions, hepatocytes undergo apoptosis, whereas HSCs are activated and proliferate [47][48][49][50]. These apoptotic hepatocytes release various cytokines to stimulate HSCs and inflammation [16,17]. Hh ligands released by apoptotic hepatocytes stimulate Hh-responsive cells, such as HSCs and liver progenitor cells [18,19].…”

“…The activated Glis act as transcriptional factors and turn on their own signaling pathway and pro-fibrotic response-related genes. Hh signaling, which is rarely detected in healthy adult livers, is activated in response to liver damage and orchestrates tissue remodeling [16,17]. Apoptotic hepatocytes in the injured liver secrete Hh ligands, Ihh, and Shh, which trigger HSC activation by turning on the Hh signaling pathway in HSCs [15,18,19].…”

“…These Hh-responsive HSCs accelerate HSC transition into MF-HSCs in a paracrine or autocrine manner, contributing to liver fibrosis. Hh ligands are also involved in the recruitment of inflammatory cells and promote liver inflammation [16,17]. However, it remains unclear whether and how the fibrotic response occurs in malaria-infected livers.…”

Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation

“…The Hedgehog pathway is critical for liver repair and regeneration but if persistently activated, it induces liver fibrosis. 18 …”

“…First, hepatocytes express different components of the hedgehog signalling cascade, including smoothened. 21 Second, hedgehog signalling in hepatocytes can regulate osteopontin expression and secretion via a Gli1-dependent mechanism 18. Pharmacological inhibition of the hedgehog pathway using smoothened inhibitors prevents liver injury, inflammation and fibrosis in a mouse model of NASH.…”