Sphingosine 1-Phosphate Signaling as a Target in Hepatic Fibrosis Therapy

Abstract

Liver fibrosis is an excess production of extracellular matrix proteins as a result of chronic liver disease which leads to cell death and organ dysfunction. The key cells involved in fibrogenesis are resident hepatic stellate cells (HSCs) which are termed myofibroblasts after activation, acquiring contractile, proliferative, migratory and secretory capability. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with well-established effects on angiogenesis, carcinogenesis and immunity. Accumulating evidence demonstrates that this metabolite is involved in the profibrotic inflammatory process through the regulation of pleiotropic cell responses, such as vascular permeability, leukocyte infiltration, cell survival, migration, proliferation and HSCs differentiation to myofibroblasts. S1P is synthesized by sphingosine kinases (SphKs) and many of its actions are mediated by S1P specific cell surface receptors (S1P1-5), although different intracellular targets of S1P have been identified. Modulation of SphKs/S1P/S1P receptors signaling is known to result in beneficial effects on various in vivo and in vitro models of liver fibrosis. Thus, a better knowledge of the molecular mechanisms involved in the modulation of the S1P pathway could help to improve liver fibrosis therapy. In this review, we analyze the effects of the S1P axis on the fibrogenic process, and the involvement of a range of inhibitors or approaches targeting enzymes related to S1P in the abrogation of pathological fibrogenesis. All in all, targeting this pathway offers therapeutic potential in the treatment of hepatic fibrosis.

RETRACTED: Melatonin Attenuates Dysregulation of the Circadian Clock Pathway in Mice With CCl4-Induced Fibrosis and Human Hepatic Stellate Cells

“…Melatonin is a secretory product of the pineal gland that, in addition to regulating circadian rhythms, modulates several molecular pathways of inflammation, oxidative stress, and cellular injury ( Crespo et al, 2010 ; Carbajo-Pescador et al, 2011 ; González-Fernández et al, 2017b ). Melatonin suppresses activation of HSCs ( Shajari et al, 2015 ), and protects against liver fibrosis in carbon tetrachloride (CCl 4 )-treated mice through effects not solely restricted to its antioxidant property ( Crespo et al, 2015 ; San-Miguel et al, 2015 ; González-Fernández et al, 2017a ).…”

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

“…One of the other feasible strategies to target YAP in fibrosis would be to use antagonists of YAP-activating GPCRs. LPA antagonists are already in clinical development [79], the direct thrombin inhibitor dabigatran etexilate is tested in preclinical fibrosis models [38,80] and in patients with scleroderma-associated interstitial lung disease [81], and blocking S1P signalling is also considered as an attractive strategy in fibrotic disorders [82]. However, the potential of antagonists of a single GPCR might be limited, as other YAP-activating ligands and receptors can drive the pathogenic processes at the same time.…”

Global Gene Expression Profiling Reveals Isorhamnetin Induces Hepatic-Lineage Specific Differentiation in Human Amniotic Epithelial Cells

“…This pathway is reciprocally regulated by insulin through PI3K/Akt pathway. Among other enriched pathways, the mTOR pathway is involved in liver regeneration and autophagy functions ( Fouraschen et al, 2013 ), and Sphingosine 1-Phosphate Signaling pathway in liver fibrosis through regulating pleiotropic cell responses to inflammation, such as cell survival, migration, and vascular permeability ( González-Fernández et al, 2017 ). In addition, Prolactin signaling not only regulates postnatal liver growth in rodents ( Moreno-Carranza et al, 2018 ) but also regulates liver regeneration by stimulating hepatocyte proliferation, promoting angiogenesis, downregulating IL-6, and upregulating SOCS3 ( Moreno-Carranza et al, 2013 ).…”