Therapeutic targets in liver fibrosis

Abstract

Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points. antifibrotic therapy; hepatic stellate cell MECHANISMS AND MEDIATORS OF LIVER FIBROGENESIS AND FIBROSIS REGRESSIONAs our understanding of the complex biological processes that regulate liver scarring increases, points of intervention in the fibrotic cascade are relentlessly uncovered. Key mechanisms and mediators are outlined below, to highlight emerging therapeutic targets (Fig. 1). Liver Fibrogenesis and the Role of the Hepatic Stellate Cell-MyofibroblastLiver fibrogenesis is orchestrated by a heterogeneous population of profibrogenic myofibroblasts (MFBs), the majority originating from hepatic stellate cells (HSCs), following a process termed "activation." Other sources of fibrogenic cells have recently been implicated, including portal fibroblasts and cells derived from the bone marrow (including fibrocytes) (7). A more controversial phenomenon is epithelial-to-mesenchymal transition, whereby epithelial cells (hepatocytes or cholangiocytes) undergo transdifferentiation to MFBs driven by bone morphogenic protein 7 and the hedgehog pathway, respectively, as well as a series of proinflammatory mediators. The relative contribution of these diverse precursors to fibrogenesis and the timing of their recruitment are unclear but may vary by disease etiology. In normal liver, quiescent HSCs store vitamin A in lipid droplets, but i...

Comparative Characterization of Hepatic Distribution and mRNA Reduction of Antisense Oligonucleotides Conjugated with Triantennary N-Acetyl Galactosamine and Lipophilic Ligands Targeting Apolipoprotein B

“…Lipophilic ligand conjugations can enhance delivery to NP cells. NP cells consist of sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, which express disease-related genes causing inflammation (Huang et al, 2013) and fibrosis (Fallowfield, 2011). Although our findings represent an important step in advancing ligand selection tailored to the expression cells of disease-related genes, additional studies are required to isolate the sinusoidal endothelial cells and Kupffer cells as described previously (Bijsterbosch et al, 2000) and evaluate the efficacy.…”

“…Disease-related genes causing hyperlipidemia and diabetes are expressed in hepatocytes, which account for a large proportion (approximately 80%) of liver volume (Sehgal et al, 2013). On the other hand, NP cells account for only a small proportion of liver volume and consist of several cell types, such as sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, that express disease-related genes causing inflammation (Huang et al, 2013) and fibrosis (Fallowfield, 2011). Several studies have been conducted to aid the development of drug delivery systems to the liver using ligand conjugation.…”

Synthesis of peptides of Carapax Trionycis and their inhibitory effects on TGF-β1–induced hepatic stellate cells

“…During fi brosis progression, the main ECM-producing cells are activated HSCs, which secrete ECM proteins including collagen I and III (17). Cross-remodeling of the ECM in the fibrotic liver is likely to be regulated by the synthesis and enzymatic degradation of the ECM.…”

Apoptosis of rat hepatic stellate cells induced by diallyl trisulfide and proteomics profiling in vitro

“…There are 3 major pathways that may help eliminate the activated HSCs: apoptosis, senescence, or reversal to an inactivated phenotype. In recent years, induction of apoptosis to eliminate HSCs has been suggested to be effective in the control of hepatic fibrosis (Fallowfield 2011;Tacke and Weiskirchen 2012). Diallyl trisulfide (DATS; 3-(prop-2-enyltrisulfanyl)prop-1-ene, CH 2 =CHCH 2 -SSS-CH 2 CH=CH 2 , molecular weight 178.33), a characteristic flavor produced by garlic, contains 3 sulfur atoms with 2 allyl groups.…”