Gas6/TAM Signaling Components as Novel Biomarkers of Liver Fibrosis

Abstract

Liver fibrosis consists in the accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells. This is commonly the result of chronic liver injury repair and represents an important health concern. As liver biopsy is burdened with many drawbacks, not surprisingly there is great interest to find new reliable noninvasive methods. Among the many are new potential fibrosis biomarkers under study, some of the most promising represented by the growth arrest-specific gene 6 (Gas6) serum protein and its family of tyrosine kinase receptors, namely, Tyro3, Axl, and MERTK (TAM). Gas6/TAM system (mainly, Axl and MERTK) has in fact recently emerged as an important player in the progression of liver fibrosis. This review is aimed at giving an overall perspective of the roles played by these molecules in major chronic liver diseases. The most promising findings up to date acknowledge that both Gas6 and its receptor serum levels (such as sAxl and, probably, sMERTK) have been shown to potentially allow for easy and accurate measurement of hepatic fibrosis progression, also providing indicative parameters of hepatic dysfunction. Although most of the current scientific evidence is still preliminary and there are no in vivo validation studies on large patient series, it still looks very promising to imagine a possible future prognostic role for these biomarkers in the multidimensional assessment of a liver patient. One may also speculate on a potential role for this system targeting (e.g., with small molecule inhibitors against Axl) as a therapeutic strategy for liver fibrosis management, always bearing in mind that any such therapeutic approach might face toxicity.

Soluble Axl Is a Novel Diagnostic Biomarker of Hepatocellular Carcinoma in Chinese Patients with Chronic Hepatitis B Virus Infection

“…Staufer et al [26] showed that sAxl was an accurate biomarker for advanced fibrosis and LC in comparison to established non-invasive fibrosis markers such as enhanced liver fibrosis test and transient elastography (Fibroscan). Further study showed that sAxl played an important role in the progression of liver fibrosis [27,28]. High levels of sAxl was also detected in LC group in our study which may reflect that sAxl was interrelated with fibrosis or LC.…”

Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

“…GAS6 and Axl are expressed in stellate cells and Kupffer cells, but not in hepatocytes (Couchie et al, 2005;Lafdil et al, 2006). Similarly, loss of GAS6 reduces recruitment of circulating monocytes and accumulation of myofibroblasts during liver injury, which leads to a suppression in liver inflammation and fibrosis (Lafdil et al, 2009;Smirne et al, 2019). GAS6-KO mice also display reduced liver fibrosis induced by chronic carbon tetrachloride treatment (Lafdil et al, 2009;Fourcot et al, 2011).…”

Peri̇odontal Durumun Tükürük Growth Arrest-Specific Protein 6(gas6) Düzeyi̇ Üzeri̇ne Etki̇si̇ni̇n İncelenmesi̇

“…Gas6 proteini hücre proliferasyonunu, adezyonunu, migrasyonunu, apoptotik hücrelerin makrofajlar tarafından fagositozunu ve adiposit gelişimini düzenlemektir. 2 Tüm bu görevler Gas6"nın oto-immün hastalıklar, metabolik bozukluklar ve kanser oluşumundaki rolünü düşündürmektedir. Lumeng ve ark.…”