A Functional Role of GAS6/TAM in Nonalcoholic Steatohepatitis Progression Implicates AXL as Therapeutic Target

Abstract

GAS6 signaling through AXL receptor contributes to the progression of nonalcoholic steatohepatitis (NASH). Soluble AXL significantly increases both in NASH patients and mouse models. Experimental AXL inhibition by bemcentinib diminishes inflammation and fibrosis, supporting its therapeutic use in NASH.BACKGROUND AND AIMS: GAS6 signaling, through the TAM receptor tyrosine kinases AXL and MERTK, participates in chronic liver pathologies. Here, we addressed GAS6/TAM involvement in Non-Alcoholic SteatoHepatitis (NASH) development.METHODS: GAS6/TAM signaling was analyzed in cultured primary hepatocytes, hepatic stellate cells (HSC) and Kupffer cells (KCs). Axl -/-, Mertk -/and wild-type C57BL/6 mice were fed with Chow, High Fat Choline-Deficient Methionine-Restricted (HFD) or methionine-choline-deficient (MCD) diet. HSC activation, liver inflammation and cytokine/chemokine production were measured by qPCR, mRNA Array analysis, western blotting and ELISA. GAS6, soluble AXL (sAXL) and MERTK (sMERTK) levels were analyzed in control individuals, steatotic and NASH patients. RESULTS:In primary mouse cultures, GAS6 or MERTK activation protected primary hepatocytes against lipid toxicity via AKT/STAT-3 signaling, while bemcentinib (small molecule AXL inhibitor BGB324) blocked AXL-induced fibrogenesis in primary HSCs and cytokine production in LPS-treated KCs. Accordingly; bemcentinib diminished liver inflammation and fibrosis in MCD-and HFD-fed mice. Upregulation of AXL and ADAM10/ADAM17 metalloproteinases increased sAXL in HFD-fed mice. Transcriptome profiling revealed major reduction in fibroticand inflammatory-related genes in HFDfed mice after bemcentinib administration. HFD-fed Mertk -/mice exhibited enhanced NASH, while Axl -/mice were partially protected. In human serum, sAXL levels augmented even at initial stages, whereas GAS6 and sMERTK increased only in cirrhotic NASH patients. In agreement, sAXL increased in HFD-fed mice before fibrosis establishment, while bemcentinib prevented liver fibrosis/inflammation in early NASH.CONCLUSION: AXL signaling, increased in NASH patients, promotes fibrosis in HSCs and inflammation in KCs, while GAS6 protects cultured hepatocytes against lipotoxicity via MERTK. Bemcentinib, by blocking AXL signaling and increasing GAS6 levels, reduces experimental NASH, revealing AXL as an effective therapeutic target for clinical practice.

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.…”

Role of Vitamin K-Dependent Factors Protein S and GAS6 and TAM Receptors in SARS-CoV-2 Infection and COVID-19-Associated Immunothrombosis

“…Over the last decade, TAM receptors and ligands have been strongly connected to different human pathologies [ 63 , 81 , 88 , 102 , 118 , 119 ]. The TAM system, first related to the immune system and cancer, and more recently in molecular processes ranging from induction of fibrosis to cytokine control, is now establishing new links to other diseases.…”

Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer

“…At the same time, Axl + monocytes are elevated in patients with cirrhosis (Brenig et al, 2020), and serum Gas6 and sAxl levels are elevated in patients with hepatitis C virus and alcoholic liver disease (Barcena et al, 2015). Divergent roles for Axl and Mer have been reported in chronic models of fibrosis, where Mertk −/− mice exhibited enhanced NASH development when fed a high-fat diet, whereas Axl −/− mice were protected (Tutusaus et al, 2019). These multiple findings notwithstanding, the general importance of TAM receptor signaling to both normal liver physiology and to acute, rapid-onset liver insults has not been assessed.…”