Mechanisms of hepatic fibrogenesis

Abstract

Multiple etiologies of liver disease lead to liver fibrosis through integrated signaling networks that regulate the deposition of extracellular matrix. This cascade of responses drives the activation of hepatic stellate cells (HSCs) into a myofibroblast-like phenotype that is contractile, proliferative and fibrogenic. Collagen and other extracellular matrix (ECM) components are deposited as the liver generates a wound-healing response to encapsulate injury. Sustained fibrogenesis leads to cirrhosis, characterized by a distortion of the liver parenchyma and vascular architecture. Uncovering the intricate mechanisms that underlie liver fibrogenesis forms the basis for efforts to develop targeted therapies to reverse the fibrotic response and improve the outcomes of patients with chronic liver disease.

Figure 1. Stellate cell activation through “classic” mechanisms (upper panel) and emerging new mechanisms (lower panel)

The HSC is the central effector in hepatic fibrosis and undergoes activation through a two-phase process. Initial liver injury results in hepatocyte cell apoptosis with generation of apoptotic bodies, reactive oxygen species, and paracrine stimulation of HSCs. Additionally, LPS from the gut can simulate HSCs. These initial stimuli allow the cell to become sensitized to additional activation by upregulating various receptors and is termed the initiation phase. Subsequently, it is able to secrete autocrine and paracrine growth factors, chemokines, and ECM. Maintenance of HSC activation is termed the perpetuation phase, and involves changes in HSC behavior, including proliferation, chemotaxis, fibrogenesis, and contractility. (A) Among other cell types that may contribute to ECM production, fibrocytes derived from the bone marrow are believed to transdifferentiate into myofibroblasts. (B) Mechanical stiffness of the ECM can be sensed by and activate HSCs. (C) The contribution of dendritic cells to fibrosis is complex and not yet well understood, however, they can activate NK cells. HSCs become sensitized to NK cell mediate apoptosis after cellular activation causes downregulation of their inhibitory MHC class I molecules. (D) New evidence suggests fibrosis can regress through reversion, senescence or apoptosis of HSCs.

Figure 2. Current and emerging signaling pathways regulating HSC activation

PDGF signals partially through ERK activation and also through AKT via mTOR mediated protein synthesis regulation. PDGF activation also allows for influx of Ca²⁺ ions, which contributes to gene regulation. In addition to PDGF, several other growth factors can activate tyrosine receptors, which lead to Akt activation and then either mTOR or JNK activation. TGF-β recruits Smad2/3, leading to their phosphorylation and stimulation of fibrogenic gene expression. Emerging pathways of importance to fibrosis include contributions from adiopkines (leptin), neuroendocrine signals (2-AG), TLR signaling, and angiogenic signals (VEGF), among others.