Alteracions de la paraoxonasa-1 en l'hepatopatia crònica

Identificador:  TDX:521

Handle: https://hdl.handle.net/20.500.11797/TDX521

Autores:  Marsillach López, Judit

Resumen:
The family of serum paraoxonases (PON) consist of three enzymes: PON1 (the most investigated member), PON2 and PON3. In humans, PON1 expression is mainly found in the liver, and circulates tightly bound to HDL. PON1 is a polymorphic enzyme that is able to degradate organophosphates and different type of esters, lactones and xenobiotics, but its physiological function is to hydrolise lipid peroxides. It has also an antiinflamatoy role since it can attenuate MCP-1 (a proinflamatory chemokine) secretion. Oxidative stress and inflammation play key roles in the development of liver diseases. Since PON1 has a protective effect against oxidative stress, it could be plausible to find an association between PON1 and chronic hepatic diseases.<br/>Aims of the Thesis: a) to investigate the presence of alterations in PON1 activity and expression in human and experimental chronic hepatic diseases, and to study the molecular mechanisms involved; b) to evaluate a new enzymatic assay using a non toxic substrate that measures PON1 lactonase activity; c) to assess the diagnostic accuracy of the measurement of serum PON1 activity in the clinic evaluation of liver diseases.<br/>Conclusions: 1) PON1 could regulate oxidative stress by lipid peroxides degradation; inflammation, by acting as a barrier against MCP-1 induced inflammation; and cell apoptosis, by its relationship with the increase of sFAS, the soluble form of FAS receptor 2) Serum PON1 activity in patients with chronic liver disease could decreased as a consequence of alterations in the size and composition of HDL, and/or an increase of oxidative stress 3) Serum and hepatic PON1 expression would increase because of the decrease in HDL synthesis, and the decrease of cellular proteolysis 4) Serum PON1 lactonase activity measurement, using TBBL as a susbtrate, is a reliable, non-toxic, semi-automated assay, and is less influenced by genetic polymorphisms than PON1 esterase activity using paraoxon 5) Serum PON1 activity measurement has a high diagnostic accuracy and may contribute significantly to the evaluation of liver function in the clinical setting.