Influence of paraoxonase-1 deficiency on metabolic alterations and inflammation

Identifier:  TDX:2450

Handle: https://hdl.handle.net/20.500.11797/TDX2450

Authors:  Garcia Heredia, Anabel

Abstract:
Non-communicable diseases (NCD) are non-infectious and non-transmissible chronic diseases, such as diabetes, cancer and cardiovascular disease. They share common molecular mechanisms including oxidative stress, inflammation and metabolic alterations. NCD complications are interrelated, increasing risk to develop other comorbidities such as non-alcoholic fatty liver disease (NAFLD) and atherosclerosis.. NAFLD is associated with insulin resistance and subclinical atherosclerosis, that together with oxidative stress are considered driving factors in the progression of NAFLD to NASH (non-alcoholic steatohepatitis). The paraoxonase (PON) family of enzymes is an important endogenous antioxidant system implicated in protection against oxidative damage and lipid peroxidation, contribution to innate immunity, bioactivation of drugs, detoxification of reactive molecules, modulation of endoplasmic reticulum stress, and regulation of cell proliferation/apoptosis. We hypothesize that PON1 deficiency is associated to severe metabolic disturbances that may be related to inflammation and the comorbidities of some NCD, such as NAFLD and atherosclerosis. In Study 1, we investigated the effect of PON1 deficiency on histological alterations and hepatic metabolism in mice fed a high-fat high-cholesterol diet. Results showed that PON1 seems to have an important protective role in the liver which may have clinical relevance since reduced serum and liver PON1 activity is an early alteration in patients with liver impairment. In Study 2 we investigated the influence of PON1 on metabolic alterations when endothelial cells are incubated with oxLDL . The results showed that HDL from PON1 deficient mice has an impaired capacity to protect endothelial cells from oxLDL, triggering important metabolic disturbances. As there are controversial results about the effects of metformin in patients with liver impairment, in Study 3, we wanted to test metformin effects on the liver of PON1 deficient mice. Results showed that metformin administration produces undesirable effects in the liver of PON1 deficient mice, aggravating inflammation and steatosis.