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Exploiting the MSP-AMPK pathway for amelioration of NASH (MANASH)
Date du début: 1 mars 2013, Date de fin: 28 févr. 2015 PROJET  TERMINÉ 

"BACKGROUNDNon–alcoholic steatohepatitis (NASH) is the hepatic event of the metabolic syndrome and is characterized by steatosis and inflammation. Although our understanding of the disease mechanisms has progressed, the therapy options for treatment of NASH remain poor. AMP-activated protein kinase (AMPK) is an important integrator of signals managing energy balance and acts as a protective response to energy stress during metabolic deregulations. Pharmacologic AMPK activation is a well-established treatment strategy against the metabolic syndrome and has been reported to ameliorate steatosis, but accumulating evidence suggests that global AMPK activation is undesirable, especially because of affecting appetite. Macrophage-stimulating protein (MSP) is a multifunctional serum factor secreted from liver cells and a ligand for Recepteur d'origine nantais (RON) receptor tyrosine kinase to initiate downstream signaling pathways in an autocrine fashion. MSP exhibits anti-inflammatory properties on macrophages. Interestingly, MSP-deficient mice on normal diet develop hepatic steatosis. However, the role of MSP in normal liver metabolism and metabolic syndrome remained underexplored. Previous studies by the applicant demonstrated MSP as a negative regulator of hepatic gluconeogenesis and of inflammatory responses, both via AMPK activation.HYPOTHESISMSP-mediated activation of AMPK is an effective treatment option against NASH.OBJECTIVES1) Investigate the molecular mechanism and metabolic/anti-inflammatory action of MSP-mediated AMPK activation in cultured hepatocytes and macrophages.2) Stimulate the MSP/AMPK pathway in liver to assess the potential of ameliorating NASH in relevant mouse models.DELIVERABLES1) Identification of novel upstream regulators of AMPK downstream of MSP/RON.2) Appraisal of MSP for possible treatment of NASH in humans."