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Staging NAFLD: Diagnostic and Therapeutic Value of TAM Signaling

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Staging NAFLD: Diagnostic and Therapeutic Value of TAM Signaling

A sedentary lifestyle and the overconsumption of calorie-dense refined meals reflect today’s modern society. These factors undoubtedly explain the global epidemic of overweight and metabolic syndrome, whose hepatic consequence is the so-called nonalcoholic fatty liver disease (NAFLD). This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), the latter characterized by inflammation, injury, and hepatic fibrosis. However, because of the limitations of the current clinical diagnosis of liver fibrosis, there is an urgent unmet need for novel potential biomarkers.

It was not until 1995 that the family of receptor tyrosine kinases (RTKs), TYRO3, AXL, and MERTK (TAM) was no longer considered orphan receptors.1x1Graham, D.K., DeRyckere, D., Davies, K.D., and Earp, H.S. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer. 2014;
14: 769–785
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In this issue of Cellular and Molecular Gastroenterology and Hepatology, Tutusaus et al2x2Tutusaus, A., de Gregorio, E., Cucarull, B., Cristobal, H., Areste, C., Graupera, I., Coll, M., Colell, A., Gausdal, G., Lorens, J.B., Garcia de Frutos, P., Morales, A., and Mari, M. A functional role of GAS6/TAM in nonalcoholic steatohepatitis progression implicates AXL as therapeutic target. Cell Mol Gastroenterol Hepatol. 2020;
9: 349–368
Abstract | Full Text | Full Text PDF | Scopus (1)
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Nonetheless, the functional relevance of the TAM system during hepatic fibrogenesis was unknown. Several investigators4x4Lafdil, F., Chobert, M.N., Deveaux, V., Zafrani, E.S., Mavier, P., Nakano, T., Laperche, Y., and Brouillet, A. Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice. J Hepatol. 2009;
51: 55–66
Abstract | Full Text | Full Text PDF | PubMed | Scopus (25)
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Thus, AXL as a theranostic target for CLD needed to be examined thoroughly. Constitutive-deleted AXL mice challenged chronically with CCl4 showed decreased HSC activation in vitro and liver fibrogenesis.8x8Barcena, C., Stefanovic, M., Tutusaus, A., Joannas, L., Menendez, A., Garcia-Ruiz, C., Sancho-Bru, P., Mari, M., Caballeria, J., Rothlin, C.V., Fernandez-Checa, J.C., de Frutos, P.G., and Morales, A. Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. J Hepatol. 2015;
63: 670–678
Abstract | Full Text | Full Text PDF | PubMed | Scopus (36)
| Google ScholarSee all References

In contrast, MERKT-ablated mice showed aggravated liver damage,2x2Tutusaus, A., de Gregorio, E., Cucarull, B., Cristobal, H., Areste, C., Graupera, I., Coll, M., Colell, A., Gausdal, G., Lorens, J.B., Garcia de Frutos, P., Morales, A., and Mari, M. A functional role of GAS6/TAM in nonalcoholic steatohepatitis progression implicates AXL as therapeutic target. Cell Mol Gastroenterol Hepatol. 2020;
9: 349–368
Abstract | Full Text | Full Text PDF | Scopus (1)
| Google ScholarSee all References

The next obvious question is whether hepatic injury and inflammation could be diagnosed using markers of the TAM system. Barcena et al8x8Barcena, C., Stefanovic, M., Tutusaus, A., Joannas, L., Menendez, A., Garcia-Ruiz, C., Sancho-Bru, P., Mari, M., Caballeria, J., Rothlin, C.V., Fernandez-Checa, J.C., de Frutos, P.G., and Morales, A. Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. J Hepatol. 2015;
63: 670–678
Abstract | Full Text | Full Text PDF | PubMed | Scopus (36)
| Google ScholarSee all References

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