Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets

Abstract

Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.

Keywords: Etiology; Fibrosis; Hepatic stellate cells; Liver cirrhosis; Pathology; Treatment.

Figure 1

Initiation, progression, and resolution of liver fibrosis involving hepatic stellate cells. Upon various types of chronic injury - including that caused by alcohol, viral and schistosome infection, nonalcoholic steatohepatitis (NASH), and other factors - hepatic stellate cells (HSCs) transdifferentiate from quiescent HSCs to activated HSCs, the latter of which secrete abundant extracellular proteins that contribute to liver fibrosis. Liver fibrosis is thought to be a reversible condition owing to the elimination of causative agents and different strategies of limiting HSC activation; however, they cannot totally return to a quiescent status of the naive HSCs. Instead, they exhibit a pre-activated intermediate condition with an increased sensitivity to injury. Thus, preventing recurrent chronic liver injury is of great importance in patients undergoing treatment for liver fibrosis. Untreated or relapsed fibrosis progresses to liver cirrhosis, which often requires hepatic transplantation.

Figure 2

Roles of interleukin-30, hydrogen peroxide inducible clone 5, and cholesterol acyltransferase 1 in liver fibrosis.

Figure 3

Roles of the Wnt, TGF-β/Smad, and Gas6/Axl signaling pathways in the progression of liver fibrosis.

Figure 4

Mechanism of action of three potential therapeutic drugs-ursolic acid, 24-nor-ursodeoxycholic acid, and resveratrol-for treating fibrosis.