Farnesoid X Receptor Critically Determines the Fibrotic Response in Mice but Is Expressed to a Low Extent in Human Hepatic Stellate Cells and Periductal Myofibroblasts

Fickert, Peter; Fuchsbichler, Andrea; Moustafa, Tarek; Wagner, Martin; Zollner, Gernot; Halilbasic, Emina; Stöger, Ulrike; Arrese, Marco; Pizarro, Margarita; Solı́s, Nancy; Carrasco, Gonzalo; Caligiuri, Alessandra; Sombetzki, Martina; Reisinger, Emil C.; Tsybrovskyy, Oleksiy; Zatloukal, Kurt; Denk, Helmut; Jaeschke, Hartmut; Pinzani, Massimo; Trauner, Michael

doi:10.2353/ajpath.2009.090114

Cited by 156 publications

(134 citation statements)

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“…receptor) (65,66). TCA-induced activation of PFs appears to be specific, and stimulation with other bile acids (TUDCA, DCA, TCDCA, TbMCA, CA) did not induce fibrogenic gene expression in PFs.…”

Section: Ahscs and Apfs Contribute Differently To Liver Fibrosis Of Dmentioning

confidence: 83%

Origin of myofibroblasts in the fibrotic liver in mice

Iwaisako

Jiang

Zhang³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

450

461

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Significance Liver resident activated hepatic stellate cells (aHSCs), and activated portal fibroblasts (aPFs) are the major source of the fibrous scar in the liver. aPFs have been implicated in liver fibrosis caused by cholestatic liver injury, whereas fibrosis in hepatotoxic liver injury is attributed to aHSCs. However, the contribution of aPFs to cholestatic fibrosis is not well characterized because of difficulties in cell purification and the lack of identified aPF-specific markers. We have developed a novel flow cytometry-based method of aPFs purification from the nonparenchymal cell fraction of collagen-α1(I)-GFP mice and have identified potential aPF-specific markers. The goal of this study is to determine whether aPFs contribute to cholestatic liver fibrosis and identify the mechanism(s) of their activation.

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Section: Ahscs and Apfs Contribute Differently To Liver Fibrosis Of Dmentioning

confidence: 83%

Origin of myofibroblasts in the fibrotic liver in mice

Iwaisako

Jiang

Zhang³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

450

461

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“…The antifibrotic potential of stimulating FXR is unproven and the recent observation that there is no FXR expression in mouse or human HSCs and MFBs in liver fibrosis suggests that these cells are not direct therapeutic targets for FXR ligands (5).…”

Section: Prevention Of Hsc Activation And/or Proliferationmentioning

confidence: 99%

Therapeutic targets in liver fibrosis

Fallowfield

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

115

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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...

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“…[5][6][7] In addition, it has been suggested, although controversial, that FXR modulates liver fibrosis. 8,9 The study published herein demonstrates a reduced FXR expression in the two murine models of cirrhosis. More important, acute (24 hours) and semichronic (10 days) systemic administration of OCA effectively activates FXR, as shown by the increase in its downstream effector small heterodimer partner (SHP), and produces a significant reduction in portal pressure in both models of cirrhosis.…”

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confidence: 99%