The liver is innervated by sympathetic, parasympathetic, and peptidergic nerves, which contain afferent and efferent fibers. Several neuropeptides have been identified in the liver such as, neuropeptide Y (NPY), substance P (SP), and calcitonin gene-related peptide (CGRP). In particular, SP is synthesized by the liver, where it can regulate different activities including inflammation and proliferation. NAFLD is characterized by hepatic steatosis, liver inflammation, cirrhosis and ultimately liver failure. During this disease, ductular reaction (DR), represented by the activation of hepatic stem/progenitor cells (HpSCs), has been correlated with the severety of hepatic damage. It has been shown that SP plasma levels are elevated in patients with nonalcoholic cirrhosis. Knockout of SP receptor (NK-1R) reduces cholangiocyte hyperplasia and expression of fibrogenic markers in bile duct¿ligated (BDL) mice. However, no studies exist regarding the role of the SP/NK-1R axis in the development of non-alcoholic fatty liver disease. For that reason, the general aim of the present project will be to define the role of this axis in the activation of HpSC niche during NAFLD. Using experimental models and human biopsies, specific objectives will be: i) to evaluate liver morphology and hepatic steatosis in the different samples; ii) to investigate the localization of SP and NK1R in the different hepatic cells: hepatocytes, cholangiocytes, hepatic stellate cells (HSCs) and macrophages; iii) to study the expression of membrane metallopeptidase (MME); iv) to individuate the presence of inflammation markers, such as TNF-¿ and IL-6. Data obtained from this project will lead i) to understand cellular mechanisms at the basis of NAFLD progression; ii) to clarify the pathogenesis of cholangiopathies and biliary fibrosis; iii) to individuate novel molecular tools and therapeutic approaches targeting NAFLD.
